BACTERIA, FUNGI, AND VIRUSES

National Research Council (US) Committee on Infectious Diseases of Mice and Rats

NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.

National Research Council (US) Committee on Infectious Diseases of Mice and Rats. Companion Guide to Infectious Diseases of Mice and Rats. Washington (DC): National Academies Press (US); 1991.

Companion Guide to Infectious Diseases of Mice and Rats.

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BACTERIA, FUNGI, AND VIRUSES

Adenoviruses

Agent. DNA virus. Two strains, MAd-1 and MAd-2 (formerly called FL and K87, respectively), are recognized.

Animals Affected. Mice and rats.

Epizootiology. Prevalence is probably low. MAd-1 is shed in urine, and MAd-2 is shed in feces. Transmission is by the oral route.

Clinical. Natural infection does not cause clinical disease.

Pathology. There are no pathologic lesions associated with natural infections of MAd-1. Viral inclusions in intestinal mucosa are associated with MAd-2 infections.

Diagnosis. The preferred diagnostic procedures are the ELISA and the IFA test, which test sera for antigens of both MAd-1 and MAd-2. Presumptive diagnosis of MAd-2 can be made by demonstration of characteristic intranuclear inclusions in histologic sections of intestinal epithelium. A fluorescent antibody method has been used for detecting MAd-2 antigen in the intestine. Definitive diagnosis requires virus isolation in tissue culture.

Control. Cesarean derivation and barrier maintenance may be necessary for eliminating either virus strain.

Interference with Research. MAd-1 can produce extensive persistent lesions in the kidneys of adult mice and render them more susceptible to experimental Escherichia coli-induced pyelonephritis. MAd (strain not given) has been reported to accelerate experimental scrapie in mice.

Bacillus piliformis

Agent. Unclassified gram-negative bacterium, having vegetative and spore forms.

Animals Affected. Mice, rats, gerbils, hamsters, guinea pigs, rabbits, cats, dogs, nonhuman primates, horses, and others.

Epizootiology. Prevalence in the United States is unknown. Natural infection is thought to be caused by ingestion of spore-contaminated food or bedding.

Clinical. Subclinical infection is probably more common than clinical disease (commonly called Tyzzer's disease). Contributors to clinical disease include poor sanitation, overcrowding, transportation stress, food deprivation, dietary modifications, and altered host immune status. Clinical disease occurs most frequently in sucklings and weanlings, but animals of any age can be affected. Morbidity and mortality vary from low to high. Unexpected deaths, watery diarrhea, pasting of feces around the perineum, ruffled fur, and inactivity are the most common signs. Homozygous female and hemizygous male CBA/N-xid and C3. CBA/N-xid mice, which are deficient in a specific subpopulation of B cells, are highly susceptible, whereas T-cell-deficient athymic (nu/nu) mice are as resistant as immunocompetent mice.

Pathology. Primary infection occurs in the ileum and cecum, followed by ascension of the organisms by the portal vein to the liver and bacteremic spread to other tissues, most notably the myocardium. The organism preferentially replicates in the intestinal epithelium, smooth muscle, hepatocytes, and myocardium, but the degree of replication (and lesions) varies considerably between animals and between species. Intestinal lesions are usually more severe in rats than in mice. Myocardial lesions occur inconsistently. Gross lesions range from none to severe involvement of the intestine, liver, and/or heart. In mice, the most consistent finding is multiple pale to yellow foci in the liver. Infrequently, the ileum and cecum appear thickened, edematous, and hyperemic, and the myocardium contains circumscribed pale gray areas. Lesions in rats are similar, except that the ileum often appears dilated, atonic, and edematous (megaloileitis). The mesenteric lymph nodes are usually enlarged. In the ileum, in the cecum, and sometimes in the proximal colon, there is mild to severe loss of the mucosal epithelium, with blunting of villi in the ileum, thinning of the surface epithelium, and severe ulceration and hemorrhage. In more advanced stages, there is hyperplasia of crypt epithelium. Transmural acute to subacute inflammation can occur in areas of severe epithelial loss. In the liver there are multiple foci of coagulative necrosis that are rapidly converted to microabscesses. If the myocardium is affected, there is focal to diffuse myocardial necrosis with acute to subacute inflammation. In affected tissues, the characteristic large, filamentous bacilli are best demonstrated histologically in the cytoplasm of viable cells along the margin of necrotic tissues by the use of silver strains (Warthin- Starry or methenamine silver).

Diagnosis. Diagnosis of clinical disease is based on finding typical gross and microscopic lesions and characteristic organisms in silver-stained histologic sections. Both the IFA and the CF tests have been used for the diagnosis of subclinical infections, but neither test is available commercially in the United States. Alternatively, weanling animals can be immunosuppressed by the administration of 100- 200 mg/kg cortisone acetate. Subclinical infection, if present, will become active disease, and characteristic lesions and organisms can be demonstrated histologically 7 days after cortisone administration. The presence of B. piliformis in tissues can be demonstrated by the finding of characteristic lesions and organisms histologically 5-7 days following inoculation of the tissue into gerbils or into homozygous xid female or hemizygous xid male mice.

Control. Cesarean-derivation and barrier-maintenance procedures, reduction of stress, and good sanitation procedures appear to minimize the occurrence of clinical disease. Good sanitation practices, avoidance of crowding, autoclaving of food and bedding, and the use of 0.3% sodium hypochlorite for disinfecting room surfaces are recommended for reducing spore contamination in conventional animal facilities. Oral administration of tetracycline can be helpful in controlling losses during outbreaks.

Interference with Research. Tyzzer's disease can cause high mortality in breeding colonies of mice and in mice used in long-term carcinogenesis studies. Administration of cortisone or adrenocorticotropic hormone, whole-body x-irradiation, transplantation of ascites tumors, and a high-protein diet can induce clinical disease. Tyzzer's disease alters the pharmacokinetics of warfarin and trimethoprim and the activity of hepatic transaminases.

Cilia-Associated Respiratory Bacillus

Agent. Gram-negative bacterium.

Animals Affected. Laboratory rats and mice, wild rats (Rattus norvegicus), African white-tailed rats (Mystromys albicaudatus), and rabbits.

Epizootiology. Unknown.

Clinical. Clinical manifestations in rats are similar to those of severe murine respiratory mycoplasmosis (MRM) and can include hunched posture, ruffled coat, inactivity, head tilt, and accumulation of prophyrin pigment around the eyes and external nares. No description of clinical disease in mice has been published.

Pathology. In those instances in which cilia-associated respiratory (CAR) bacillus has been found in rats with natural disease, Mycoplasmapulmonis also was present. It is possible that M. pulmonis was the primary pathogen and the CAR bacillus increased disease severity. It is not known whether the CAR bacillus alone can cause natural clinical disease.

The predominant lesions in rats are those of advanced MRM due to M. pulmonis with some additional distinctive features. Severe bronchiectasis and bronchiolectasis, pulmonary abscesses, and atelectasis are associated with the accumulation of purulent or mucopurulent exudate in airways. An abundance of mucus often is present in peribronchiolar alveoli. Multifocal necrosis and acute inflammation of bronchiolar and bronchial epithelia often progress to severe granulomatous inflammation in airway walls and abscess formation in airway lumens. Disordered repair may result in distorted, scarred bronchioles and bronchiolitis obliterans. The ciliated border of the respiratory epithelium in affected airways often appears quite dense in hematoxylin- and eosin-stained sections because of the large numbers of CAR bacilli present between the cilia. The CAR bacillus can also be found on epithelial surfaces associated with MRM lesions in nasal passages, larynx, trachea, and middle ears. CAR bacillus-associated respiratory lesions similar to those seen in rats have been reported in C57BL/6J-ob/ob mice.

Diagnosis. Recognition of the argyrophilic CAR bacillus in Warthin-Starry silver-stained histologic sections of affected lungs has been the main diagnostic method used. The organism also can be demonstrated by transmission electron microscopy. The ELISA and the IFA test for this infection are in use in some laboratories but have not been fully evaluated.

Control. The infection probably can be eliminated by cesarean derivation, but definitive data are not available.

Interference with Research. Uncertain. The organism might be an important contributor to the morbidity and mortality caused by MRM in rats.

Citrobacterfreundii Biotype 4280

Agent. Gram-negative bacterium. Usually considered an opportunistic pathogen.

Animals Affected. Mice.

Epizootiology. Transmission is presumed to be by the fecal-oral route. The organism is rarely found in cesarean-derived, barrier-maintained mice.

Clinical. Signs of disease are nonspecific and include ruffled fur, listlessness, weight loss, stunting, pasty feces around the anus and perineum, and rectal prolapse. Suckling mice are more susceptible to disease than are adults. Mortality can reach 60%, and the occurrence of rectal prolapse can reach 15%. Mortality is significantly higher in C3H/HeJ than in DBA/2J, C57BL/6J, or N:NIHS (Swiss) mice.

Pathology. Infection in mice lasts only about 4 weeks. Even if the infection is eliminated as early as 2 days postinfection by administration of neomycin sulfate or tetracycline hydrochloride, mucosal hyperplasia still occurs. Presence of the infection in the intestine for 10 days results in maximum hyperplasia. The descending colon is most commonly affected, but the entire colon and cecum can be involved. Grossly, affected bowel is thickened and rigid in appearance. Microscopically, crypt height is increased threefold, mitotic activity is increased, goblet cells are decreased, and basophilia of the epithelium is increased. Crypt abscesses are common, and mucosal erosions and ulcers can occur. The occurrence of necrotizing and inflammatory lesions tends to parallel mortality. Variable numbers of neutrophils or mononuclear leukocytes can be present in the lamina propria, but there is often a paucity of inflammatory cells. Goblet-cell hyperplasia with mucinous distension of crypts and streaming of mucin into the gut lumen can occur during regression of mucosal hyperplasia.

Diagnosis. Diagnosis is by demonstration of characteristic lesions in the large intestine and isolation of organisms of the pathogenic biotype.

Control. Definitive data are lacking. Control probably requires depopulation and restocking with cesarean-derived mice. Neomycin or tetracycline administered in drinking water reduces losses during outbreaks but probably does not completely eliminate infection.

Interference with Research. The cytokinetics of the mucosal epithelium in the large intestine is profoundly altered in infected mice. Susceptibility to the carcinogen 1,2-dimethylhydrazine is increased, and the latent period for neoplasia induction is reduced.

Corynebacterium kutscheri

Agent. Gram-positive bacterium.

Animals Affected. Mice, rats, and rarely guinea pigs.

Epizootiology. Persistent subclinical infections are thought to be common in conventionally reared stocks and rare in barrier-maintained stocks. The main sites of infection are probably the oropharynx, submaxillary lymph nodes, and large intestine, with transmission mainly by the fecal-oral route.

Clinical Signs. Infection is usually inapparent. Disease occurs only after the immune system is compromised by experimental procedures, dietary deficiency, or concurrent infections with other agents. Signs of clinical disease in rats are usually those of a respiratory infection: dyspnea, rales, weight loss, humped posture, and anorexia. Signs in mice are usually those of severe septicemia: dead and moribund animals. Arthritis or abscesses can occur in either species.

Pathology. Septicemia results in septic emboli in many organs. In mice, large bacterial emboli lodge in capillary beds, particularly in the kidney and liver. Embolic glomerulitis is characteristic. Abscess formation can occur at the focus of infection. In rats, bacterial emboli lodge in the capillaries of the lungs. Alveoli become packed with polymorphonuclear leukocytes and can form large necropurulent centers. Fibrinous or fibrous pleuritis often develops. Occasionally, abscesses occur in the liver, kidneys, subcutis, peritoneal cavity, and other sites.

Diagnosis. Detection of persistent subclinical infections is very difficult. Available methods are unsatisfactory for detecting persistent subclinical infections, although an ELISA has been developed that shows promise for detecting antibodies. There is also a new DNA probe method, but its usefulness has not been determined. Cortisone acetate can be given to provoke active disease, which is then diagnosed by culture of the organism, demonstration of characteristic lesions, and exclusion of other infectious agents and disease processes.

Control. Cesarean derivation and barrier maintenance are effective means of control.

Interference with Research. Infection with C. kutscheri can complicate experiments involving immunologically compromised mice or rats.

Cytomegalovirus, Mouse

Agent. Double-stranded DNA virus, family Herpesviridae.

Animals Affected. Wild mice and laboratory mice that have contracted the infection from wild mice.

Epizootiology. Prevalence in laboratory mice is uncertain but is probably very low. Transmission occurs through the saliva, and infection persists throughout life. Vertical transmission also can occur but has not been fully explained. Direct passage of the virus across the placenta to the fetus and/or transmission via germ cells have been suggested.

Clinical Signs. Natural infections are subclinical.

Pathology. In natural infections, large acidophilic intranuclear inclusions are found in salivary gland acinar and duct cells. Affected cells typically are enlarged three to four times normal. The submaxillary glands are affected most, the sublingual glands less, and the parotid glands least.

Diagnosis. The IFA and CF tests have been shown to be sensitive for acute experimental infections, and the ELISA has been shown to be sensitive for persistent experimental infections. These methods may prove useful for monitoring laboratory mice for cytomegalovirus infection in selected situations. Virus isolation can be accomplished using mouse embryo fibroblasts or other tissue culture systems.

Control. Wild mice must be excluded from rodent facilities.

Interference with Research. Natural infections have not been reported to interfere with research.

Ectromelia Virus

Agent. DNA virus, family Poxviridae.

Animals Affected. Mice.

Epizootiology. Ectromelia virus is possibly enzootic in some mouse colonies. Periodic epizootics have occurred in the United States since 1950, most commonly in research laboratories that exchange live mice and their tissues, sera, or transplantable tumors. Natural transmission is dependent on direct contact and fomites. Skin abrasions are thought to be the main route of virus entry. Infected animals begin shedding virus about 10 days postinfection when characteristic skin lesions appear. Persistent infection (carrier state) was previously thought to be important in the epizootiology of mousepox. More recent data suggest that significant numbers of virus particles are shed from skin lesions for only about 3 weeks.

Clinical. The severity of clinical disease (mousepox) varies greatly and depends on mouse strain, virus strain, length of time infection has been present in the colony, and husbandry practices. Inapparent infections occur mainly in resistant inbred mouse strains such as C57BL/6 or C57BL/10. Resistance in the these strains appears to be due to a single autosomal dominant trait. The more susceptible mouse strains include A, CBA, C3H, DBA/2, and BALB/c. Clinical manifestations include one or more of the following: ruffled hair; hunched posture; facial edema; conjunctivitis; swelling of the feet; cutaneous papules, erosions, or encrustations, mainly on the face, ears, feet, or tail; and necrotic amputation (ectromelia) of limbs or tails. Mortality varies from less than 1% to greater than 80%.

Pathology. The incubation period is 7-10 days. Virus replicates in the skin and then in the regional lymph nodes, resulting in a mild primary viremia. Virus is taken up by splenic and hepatic macrophages, where there is extensive multiplication that results in a massive secondary viremia and sometimes in death due to diffuse splenic and hepatic necrosis. Virus from the secondary viremia localizes in a wide variety of tissues, especially the skin (basal cells), conjunctiva, and lymphoid tissues. A primary lesion may appear at the site of skin inoculation about 4-7 days postinfection. Foot swelling and secondary generalized rash (pocks) may appear 7-10 days postinfection. Skin lesions heal within 2 weeks, leaving scars. In acute mousepox, there is severe necrosis of liver, spleen, lymph nodes, Peyer's patches, and thymus. Jejunal hemorrhage often results from mucosal erosions. Characteristic large eosinophilic cytoplasmic inclusions may be present in skin lesions.

Diagnosis. The ELISA is sensitive and specific in unvaccinated mice; however, it may give false-positive results in NZW and NZB mice. The HAI is relatively insensitive but does not give positive reactions to sera from mice vaccinated with the IHD-T strain of vaccinia virus. Diagnosis of acute disease is based on serologic testing of survivors or on the demonstration, using transmission electron microscopy, of characteristic large virus particles in affected tissues. Differential diagnosis of skin lesions should exclude bite wounds and loss of limbs due to Streptobacillus moniliformis. Biologic materials such as cells and blood can be screened for ectromelia virus by injecting the tissue into known pathogen-free mice followed by serologic testing.

Control. Quarantine and testing of incoming mice and mouse tissues from sources other than commercial barrier facilities are the best way to prevent the introduction of infection. In the past, the accepted practice for eradicating ectromelia virus was elimination of infected mouse colonies and all infected biologic materials, along with rigorous decontamination of rooms and equipment. Cesarean derivation of infected mouse stocks was not acceptable because intrauterine infection is known to occur in mice infected during pregnancy. More recently it has been suggested that quarantine and cessation of breeding might successfully eliminate the virus.

Vaccination with a live-virus vaccine, the IHD-T strain of vaccinia virus adapted to growth in embryonated eggs, can be useful in eliminating disease from small closed colonies where all offspring can be vaccinated by 6 weeks of age. Vaccination can protect mice from fatal disease but does not prevent infection or virus transmission.

Interference with Research. Up to 100% of the animals in an experiment can die in an explosive outbreak. Manipulations that exacerbate ectromelia virus infections or promote epizootics include experimental infection with tubercle bacilli, x-irradiation, administration of various toxic chemicals, shipping, tissue transplantation, castration, and tumors. Ectromelia virus infection can alterphagocytic response. Conversely, procedures that decrease phagocytosis can increase susceptibility to ectromelia virus, e.g., large doses of endotoxin or splenectomy.

Encephalitozoon cuniculi

Agent. A protozoan, order Microsporidia.

Animals Affected. Mice, rats, rabbits, hamsters, guinea pigs, humans, and many other mammals.

Epizootiology. Prevalence in mouse and rat stocks is not known but is thought to be very low in comparison with that in rabbits, in which the organism is considered ubiquitous. Rabbits undoubtedly provide the major source of infection for mice and rats in research facilities. Spores of E. cuniculi are shed in the urine and ingested by another host.

Clinical. Natural infections usually are inapparent.

Pathology. In cases of clinical disease, the classic lesion in rats and rabbits is meningoencephalitis with multifocal granulomatous inflammation. Activated macrophages form glial nodules in response to the organism. These nodules have necrotic centers or appear as solid sheets of cells. Varying numbers of lymphocytes and plasma cells are seen in the meninges and around vessels. The brain lesions in mice are similar, except for the lack of the granulomatous foci. The organism occurs intracellularly in the renal tubular epithelium with or without the presence of an inflammatory response. In chronic infections, focal destruction of tubules and replacement by fibrous connective tissue results in small pits on the cortical surface. Lesions in organs other than the kidney and brain are less consistent. Intraperitoneal inoculation of E. cuniculi, as when contaminated transplantable tumors are passaged, results in ascites in mice.

Diagnosis. Several serologic tests have been developed for diagnosis of the infection in rabbits; however, only the IFA and immunoperoxidase tests have been used in surveying mouse and rat colonies. Other methods used for diagnosis include detection of parasites in urine, demonstration of typical lesions and organisms in tissue sections, and an intradermal skin test.

Control. Mice and rats should not be exposed to infected rabbits. Serologic testing of adult animals with selection of E. cuniculi-free breeding stocks has been used successfully for eradicating the infection in rabbits.

Interference with Research. The histologic changes caused by E. cuniculi infection in the brain and kidneys can complicate the interpretation of lesions in studies requiring histopathology. E. cuniculi can contaminate transplantable tumors and alter host responses during tumor passage in mice. Mice experimentally infected with E. cuniculi have reduced humoral antibody titers to sheep erythrocytes, reduced proliferative spleen cell responses to mitogens, and altered natural killer cell activity.

Hantaviruses

Agent. Single-stranded RNA viruses, family Bunyaviridae, genus Hantavirus. Hantaan virus, the cause of Korean hemorrhagic fever in humans, is the prototype member of the genus and is a significant zoonotic pathogen of laboratory rodents.

Animals Affected. Natural hosts of all hantaviruses appear to be small mammals, primarily rodents. Multiple species may serve as hosts in a given geographical area, and strain of virus and likelihood of causing disease in humans vary from region to region. Thus far, about five dominant associations between hantaviruses, rodent carriers, and human diseases (if present) have been described as follows: Hantaan virus, the field mouse Apodemus agrarius, Korean hemorrhagic fever (KHF) in Korea, and the severe form of epidemic hemorrhagic fever in China; Puumala virus, the bank vole Clethrionomys glareolus, nephropathia epidemica (NE) in Eastern Europe and Scandinavia; urban and laboratory rat viruses, Rattus norvegicus, moderate disease found mostly in people in Asia but occasionally also in Europeans; Girard Point and other viruses from North and South America, Rattus norvegicus, no disease recognized in humans, although serologic evidence of infection has been found; and Prospect Hill virus, the meadow vole Microtus pennsylvanicus, no disease recognized in humans. Naturally infected laboratory rats have been the source of Hantavirus infections in research personnel in Japan, Belgium, the United Kingdom, and France.

Epizootiology. Hantaan virus appears in the lungs of its reservoir host about 10 days postinfection and subsequently appears in the urine and saliva. Peak virus shedding occurs about 3 weeks after infection, but virus can be detected in the lungs for 6 months and occasionally for up to 2 years. Aerosols are the main mode of transmission. Other hantaviruses are assumed to have similar patterns of infection in their reservoir hosts.

Hantaviruses are transmitted to humans from persistently infected rodents and other small mammals. In laboratory settings, this is usually from laboratory rats or their tumors. The major mode of transmission is by aerosols of urine, feces, or saliva containing infectious virus. Direct animal contact is not necessary. Animal bites can transmit the infection but appear to be of relatively minor importance.

Clinical. Reservoir hosts have persistent subclinical infections. Human disease has occurred only in Europe and Asia.^*

Pathology. Lesions have not been observed in reservoir hosts infected with hantaviruses. Lungs and other tissues contain large amounts of virus without morphologic changes.

Diagnosis. Since Hantavirus infections in rodents are inapparent, diagnosis is most likely to be made through health surveillance. Recommended serologic tests are the IFA test, the ELISA, and the HAl test. Noninfectious antigen should be used, and work with animals and blood products should be done in a biological safety cabinet. P3 conditions are needed for working with unconcentrated virus in small amounts. The RAP test is recommended for testing transplantable tumors and other biologic materials for Hantavirus contamination.

Control. Hantavirus infections can be prevented by obtaining animals, transplantable tumors, and other biologic materials that have been tested and found to be free of infection. Contamination of laboratory rodent stocks by wild rodents must be prevented.

Laboratory rodent stocks found to be infected with a Hantavirus should be destroyed and replaced with pathogen-free stock. Although not proven to be effective, cesarean derivation has been recommended for eliminating the infection in valuable genetic stocks.

Interference with Research. Some hantaviruses are important zoonoses.

Hepatitis Virus, Mouse

Agent. Single-stranded RNA virus, family Coronaviridae, genus Coronavirus.

Animals Affected. Mice.

Epizootiology. Mouse hepatitis virus (MHV) infection is extremely contagious; prevalence can exceed 80%. Pathogenesis is influenced by such factors as virus strain and mouse strain. Current evidence suggests that the infection runs its course in 2-3 weeks, and there is no carrier state. Transmission is by direct contact, fomites, and airborne particles. MHV is a frequent contaminant of transplantable tumors and cell lines.

Clinical. In immunocompetent mice, MHV infections are usually subclinical. Infant mice of naive breeding populations can show diarrhea and high mortality when infected with the more virulent enterotropic MHV strains. Athymic (nu/nu) mice show progressive emaciation leading to debility and death.

Pathology. Strains of MHV differ greatly in virulence and tissue tropism, and mouse strains differ greatly in susceptibility to MHV. These factors interact with host age and route and dose of virus inoculation to determine the outcome of infection. Mechanisms of host resistance to MHV infection are poorly understood. Mice are fully susceptible to the virus as neonates, but some strains acquire resistance at 2-3 weeks of age as lymphoreticular function matures. Cell-mediated immunity is important in the development of resistance; humoral immunity is considered relatively unimportant. Macrophages, interferon, and natural killer cells may also have important roles.

There are two major disease patterns: the respiratory pattern and the enteric pattern. Lesions in immunocompetent mice are present for only about 7-10 days and are usually nonspecific and subtle, particularly those associated with the respiratory pattern. In the respiratory pattern, infection involves the nasal passages and lungs; intestinal involvement is minimal. Lesions include mild olfactory mucosal necrosis, neuronal necrosis of olfactory bulbs and tracts, lymphoplasmacytic infiltrates and vacuolation in the brain, multifocal interstitial pneumonia with mild perivascular lymphoid infiltrates, and multifocal necrotizing hepatitis. In the enteric pattern, infection is primarily restricted to the bowel, with variable spread to other abdominal organs such as the liver and abdominal lymph nodes. Lesions are most severe in neonatal mice because of their relatively slow kinetics of mucosal epithelium turnover. Varying degrees of epithelial lysis and blunting of villi occur in the small intestine. Numerous multinucleate syncytial giant cells (balloon cells) can occur on the villi, as well as in the crypts. In more severe cases, there can be ulceration of the mucosa. A similar lytic process occurs in the ascending colon and cecum. Occasionally, there is multifocal necrotizing hepatitis and/or encephalitis.

MHV infection in athymic (nu/nu) or neonatally thymectomized mice becomes progressively more generalized, severe, and chronic, with involvement of many organs, including the liver, intestine, lungs, bone marrow, lymphoreticular organs, vascular endothelium, and brain. Multifocal necrosis with syncytial giant cells usually occurs in the liver. Splenomegaly may develop because of compensatory myelopoiesis, and large numbers of myelopoietic cells may appear in the liver.

Diagnosis. The ELISA is the test of choice for serologic monitoring. An IFA test is also available and is about equal in sensitivity to the ELISA. CF and serum neutralization tests are less sensitive. Heterozygotes or sentinel mice should be used to test athymic stocks, because nu/nu homozygotes do not develop CF antibody to MHV and have a weak and variable antibody response to the ELISA and the serum neutralization test. The characteristic histologic lesions of MHV infections are useful in both health surveillance and necropsy diagnosis. Virus isolation can be difficult because not all strains grow equally well in all cell lines. Transplantable tumors and other biologic materials can be screened by virus isolation or by the MAP test.

Control. Strict adherence to barrier protocol, regular health surveillance, and testing of biologic materials from mice are necessary to prevent MHV infection. Cesarean derivation and barrier maintenance traditionally have been recommended for rederivation of breeding stocks; however, these measures may be unnecessary because recent evidence suggests that the virus is present for only 2-3 weeks. Another approach is to isolate individual breeding pairs from MHV-infected populations in separate containment devices, such as filter-top cage systems, and subsequently to select seronegative progeny as breeders.

Interference with Research. MHV has been reported to alter many experimental results. Examples are alterations in immune function and hepatic enzyme activities; inhibition of lymphocyte proliferative responses in mixed lymphocyte cultures and mitogen-stimulated cells; alteration of phagocytic and tumorcidal activity; increase of hepatic uptake of injected iron; increase of susceptibility to other indigenous pathogens; activation of natural killer cells and production of interferon; delay of the increase in plasma lactic dehydrogenase activity following infection with lactic dehydrogenase virus; and occurrence of anemia, leukopenia, and thrombocytopenia. In athymic (nu/nu) mice, the virus can also cause spontaneous differentiation of lymphocytes bearing T-cell markers, alter IgM and IgG responses to sheep erythrocytes, enhance phagocytic activity of macrophages, cause rejection of xenograft tumors, impair liver regeneration after partial hepatectomy, and cause hepatosplenic myelopoiesis. Subclinical infections are exacerbated by thymectomy; whole-body irradiation; reticuloendothelial blockade by iron salts; and administration of cortisone, cyclophosphamide, antilymphocyte serum, chemotherapeutic agents, or halothane anesthesia.

H-1 Virus^*

Agent. Single-stranded DNA virus, family Parvoviridae, genus Parvovirus.

Animals Affected. Laboratory and wild rats (Rattus norvegicus).

Epizootiology. Common infection of wild and laboratory rats; prevalance exceeds 50% in some populations. Epizootiological characteristics are generally assumed to be similar to those of Kilham rat virus infection. Transmission is primarily horizontal, and virus is shed in urine, feces, nasal secretions, and milk. Transplacental infection has not been demonstrated in natural infections.

Clinical. Natural infections are inapparent.

Pathology. There are no pathologic changes associated with natural infections.

Diagnosis. The ELISA and IFA test are usually used for initial screening, followed by either the HAI, CF, or neutralization test for discriminating between H-1 virus and Kilham rat virus infections. Primary rat embryo, 324K, or BHK-21 cells can be used for virus isolation.

Control. The same measures recommended for Kilham rat virus (see page 25) should be effective in controlling H-1 virus.

Interference with Research. It might be possible for H-1 virus to alter studies of fetal development or teratogenesis, but this has not been reported to occur as a result of natural infection. H-1 virus has been reported to cause hepatocellular necrosis when rats are subjected to liver injury by hepatotoxic chemicals, parasitism, or partial hepatectomy. H-1 virus has been reported to inhibit experimental tumor induction by adenovirus 12 and dimethylbenzanthracene in hamsters.

Kilham Rat Virus

Agents. Single-stranded DNA virus, family Parvoviridae, genus Parvovirus.

Animals Affected. Laboratory and wild rats are the natural hosts.

Epizootiology. Kilham rat virus (KRV) is a common infection in wild and laboratory rats; prevalence exceeds 50% in some populations. Transmission is primarily by the horizontal route, either through direct contact or fomites. Virus is shed in urine, feces, milk, and nasal secretions. Transplacental infection is not considered important. Persistent infection can last up to 14 weeks. KRV is a frequent contaminant of cultured cell lines and transplantable tumors.

Clinical. KRV infections rarely cause clinical disease. Signs in the few instances of overt disease that have been reported include increased numbers of uterine resorption sites in pregnant dams and runting, ataxia, cerebellar hypoplasia, and jaundice in their pups. Spontaneous deaths, cerebellar hypoplasia, scrotal cyanosis, jaundice, abdominal swelling, dehydration, and other signs of severe illness have occurred in juvenile and young adult rats.

Pathology. Parvoviruses attack rapidly dividing cells. In newborn and young rats, KRV can cause jaundice, hemorrhagic infarction with thrombosis in multiple organs (including brain, spinal cord, testes, and epididymis), and cerebellar hypoplasia. Amphophilic intranuclear inclusions occur in the endothelium and other cells of affected organs. Focal necrosis, hypertrophy and vacuolar degeneration of hepatocytes, cholangitis, and biliary hyperplasia also occur. Hemorrhagic encephalopathy has been reported in naturally infected LEW rats given cyclophosphamide.

Diagnosis. The ELISA and IFA test are the most sensitive tests but do not discriminate between different serotypes of parvoviruses. The HAI, CF, and neutralization tests are used for serotype discrimination. In clinical disease, typical lesions should be demonstrated, and virus isolation should be carried out. The virus can be grown in primary rat embryo, 324K, and BHK-21 cells.

Control. The most practical approach to controlling infection is to obtain animals demonstrated free of KRV by serologic monitoring. Biologic materials should be tested for KRV infection by the MAP test. Cesarean section should be successful for rederiving valuable breeding stocks of rats because transplacental transmission is not considered important.

Interference with Research. KRV can contaminate transplantable tumors and rat cell cultures, interfere with in vitro lymphocyte responses, suppress the development of Moloney virus-induced leukemia, and alter in vitro lymphocyte responses and cytotoxic lymphocyte activity. KRV also has been reported to induce interferon production. Immunosuppression can cause clinical disease in inapparently infected rats.

Lactic Dehydrogenase-Elevating Virus

Agent. RNA virus, family Togaviridae.

Animals Affected. Mice.

Epizootiology. Wild mice presumably serve as reservoir hosts. Transmission occurs primarily during passage of contaminated tumors, cells, or other biologic materials. Lactic dehydrogenase-elevating virus (LDV) is shed in feces, urine, saliva, and milk. After the first week of infection, the virus titer in these excretions declines sufficiently to make the risk of transmission to other mice relatively low. Transplacental transmission can occur. Bite wounds increase transmission between cagemates.

Clinical. Natural infections are usually subclinical. There is lifelong viremia in which the virus is complexed to antiviral antibody and lifelong elevation in plasma lactic dehydrogenase (LDH) and other plasma enzymes. The virus causes overt disease in C58 and AKR mice that are naturally immunosuppressed because of a loss of Lyt-1,2 cells between 5 months and 1 year of age. These mice develop polioencephalomyelitis with flaccid hind limb paralysis. C58 are more susceptible than AKR mice. Inheritance of this susceptibility is thought to be polygenic, possibly involving the H-2 complex.

Pathology. Virus titer in serum peaks 12-14 hours postinfection and gradually decreases until about 2 weeks postinfection, at which time the titer stabilizes for life. Serum LDH increases to 8- to 11-fold above normal by 72-96 hours postinfection because of the decreased clearance of LDH V, one of the five LDH isozymes. It gradually declines over the next 3 months, although it remains significantly elevated for life. SJL/J mice carry a recessive trait that causes a 15- to 20-fold increase in serum LDH. The activity of several other serum enzymes is also increased but to a lesser degree than LDH. LDV selectively replicates in a small subpopulation of macrophages, the specific identity of which is not known. As a result, cellular immunity is depressed during the first few weeks of infection and gradually returns to normal after weeks or months. There is an enhanced humoral response to antigenic challenge with T-cell-dependent antigens during the first 24 hours postinfection but a diminished humoral response to such challenge 3 weeks or longer after infection. There is a similar enhanced response to early postinfection challenge with T-cell-independent antigen but no diminution of response in chronic infection, which suggests a defect in T-cell function. Circulating antigen-antibody complexes, which partially neutralize LDV, are produced by 4 weeks postinfection. These complexes are deposited in glomeruli, but they produce only a mild membranous glomerulopathy. Protective antibody is not produced. After 5 months of age, infected C58 and AKR mice develop age-dependent encephalomyelitis characterized by neuronal destruction, mononuclear infiltration, and microglial proliferation in the gray matter of the central nervous system.

Diagnosis. Diagnosis is usually based on the presence of increased plasma LDH activity. Transplantable tumors, virus inocula, and other biologic materials can be screened for LDV contamination by inoculating pathogen-free mice with the test material and performing a plasma or serum LDH assay 72-96 hours later. Virus isolation is not practical for most diagnostic purposes.

Control. Mice from commercial barrier breeding facilities are not likely to be infected. LDV-free mice can be derived from contaminated stocks by selection of animals with normal plasma LDH concentration or by cesarean derivation. LDV can be eliminated from tumors by passage of tumor cells in a rodent species other than the mouse or by maintenance of tumor cells in tissue culture.

Interference with Research. The effects of LDV on research results can be subtle and complex. Subclinical infection with LDV lasts throughout life, and the effects on many biologic endpoints can differ dramatically with time after infection. LDV-induced immunosuppression can cause an alteration in defense mechanisms against other infectious agents. It has been reported that tumor growth is enhanced early after LDV infection because of depressed cellular immunity and is influenced less during chronic infection. LDV infection also has been shown to alter the incidence and behavior of spontaneous virus-induced neoplasms, including the Bittner mammary tumor and murine sarcoma viruses; to suppress the development of urethan-induced pulmonary adenomas; and to suppress vinyl chloride-vinyl acetate-induced carcinogenesis. It has been reported to cause delayed allograft rejection, to prevent the development of experimental allergic encephalomyelitis, and to prevent autoimmune disease in NZB and (NZB x NZW)F, hybrid mice. Serum gamma globulin levels and humoral antibody responses have been shown to increase during early infection, and humoral antibody responses have been shown to decrease during chronic infection. LDV has been found to be a polyclonal lymphocyte activator during the early stages of infection.

Leukemia Viruses, Murine

Agents. RNA virus, family Retroviridae, type C oncovirus group.

Animals Affected. Laboratory and wild mice.

Epizootiology. Murine leukemia viruses (MuLVs) are integrated into the DNA of the host's sex cells and are transmitted vertically as Mendelian traits. All laboratory and wild Mus musculus are thought to harbor these viruses. Horizontal transmission is inefficient but can occur through infected saliva, sputum, urine, feces, or milk or by intrauterine infection.

Clinical. Despite the fact that all mice have endogenous MuLVs, leukemias and related malignancies occur naturally in only 1-2% of most strains. Strain susceptibility is influenced by the number of MuLV gene copies in the genome and by other genes, including Fv-1, Fv-2, In, nu, hr, and Ir. The AKR strain, for example, has a high incidence of MuLV-related spontaneous thymic lymphoma, which reaches 90% by the time the mice are 9 months of age. The most common signs of thymic lymphoma are dyspnea, peripheral lymphadenopathy, and abdominal enlargement.

Pathology. Mouse strains with a high incidence of leukemia (e.g., AKR, C58, C3H/Fa) spontaneously express high titers of ecotropic MuLV in all organs throughout life. Mouse strains with a low incidence of leukemia (e.g., BALB/c, A/J, C3H/He, CBA/J) express only low titers of virus. The mouse leukemias are, with few exceptions, actually lymphomas because they are predominantly solid tumors of lymphocytes or other hematopoietic cells. The majority of those occurring before 1 year of age are thymic lymphomas, while those seen in older mice are predominantly histiocytic (reticulum cell) lymphomas. Other types include nonthymic lymphomas, lymphatic leukemias, granulocytic leukemias, erythroleukemia, plasma cell tumors, and mast cell tumors.

Diagnosis. Diagnosis of neoplasia is based on morphologic features in histologic sections. Tumor cell types can also be determined by analysis of cell-surface antigens. Isolation and characterization of MuLVs require specialized techniques usually available only in research laboratories dedicated to viral oncology. MuLV type and group specificity can be determined by immunofluorescence of fixed cells using an appropriate panel of type- or group-specific antisera.

Control. Control measures are not usually considered useful since all mice probably have endogenous MuLV proviruses as an integral part of their genomes. Horizontal transmission is considered inefficient.

Interference with Research. The presence of MuLVs probably has little significance for most research purposes. MuLV expression and the associated occurrence of neoplasms, however, can present competing endpoints in some studies, e.g., studies of aging processes in various organs. Thus, an awareness of the incidence of spontaneous tumors in different mouse strains or the ability of specific test chemicals to induce tumors can be useful in designing some experiments. Active MuLV infection can cause suppression of humoral and cellular immunity without causing clinical disease.

Lymphocytic Choriomeningitis Virus

Agent. RNA virus, family Arenaviridae, genus Arenavirus.

Animals Affected. Wild mice are the principal reservoir hosts, but laboratory mice and Syrian hamsters also serve as important natural hosts. Humans, monkeys, dogs, rabbits, guinea pigs, rats, and chickens are susceptible to the virus.

Epizootiology. Natural lymphocytic choriomeningitis virus (LCMV) infections of laboratory mice are rare. Only infected mice and hamsters are known to transmit the virus. Both species can have chronic infections, with high concentrations of virus shed in the urine, saliva, and milk. The portals of entry are probably mucus membranes and broken skin. Vertical (transovarian and/or transuterine) transmission occurs in mice and probably in hamsters. Once introduced into a population of mice, the infection can spread to all members of that population. Since 1960 three epidemics involving at least 236 human cases have occurred in the United States, and all have been associated with Syrian hamsters, either as laboratory animals bearing transplantable tumors or as pets.^*

Clinical. Clinical signs are highly variable depending on the virus strain, the mouse strain, and the age of the mouse at the time of infection. Persistent tolerant infection is acquired if infection occurs in utero or within a few days of birth. There is lifelong viremia and shedding of virus. Transient runting can occur during the first 3 weeks of life. Thereafter, the mice appear normal. At 7-10 months of age, immune complex glomerulonephritis occurs and is associated with emaciation, ruffled fur, hunched posture, ascites, and sometimes death. Nontolerant (acute) infection is acquired if infection occurs after the first week of life when the animals are immunocompetent. Viremia occurs, but there is no shedding of virus. The outcome is either death within a few days or weeks or recovery with elimination of the virus. Natural infections in adult mice range from inapparent infection to severe disease with high mortality. Natural infections in hamsters are usually subclinical.

Pathology. T-cell, but not B-cell, activity is suppressed in persistent tolerant infection. Infectious virus circulates bound to LCMV-specific IgG and complement. These complexes accumulate in the renal glomeruli; choroid plexus; and, to a lesser degree, in synovial membranes, in blood vessel walls, and beneath the epidermis of the skin to cause late-onset disease that becomes clinically apparent around 7-10 months of age. There is generalized lymphoid hyperplasia and perivascular accumulation of lymphocytes and plasma cells in all visceral organs. In nontolerant (acute) infection, there is multifocal hepatic necrosis and generalized necrosis of lymphoid tissues. Both the morphologic lesions and elimination of the virus are due to cell-mediated immune responses involving H-2-restricted, cytotoxic T lymphocytes and possibly natural killer cells. LCMV-infected adult mice can be protected from disease by numerous immunosuppressive regimens. Athymic (nu/ nu) mice inoculated with the virus at 3-6 weeks of age do not develop disease but become persistently viremic.

Diagnosis. The serologic methods of choice are the IFA test, the micro plaquereduction test for neutralizing antibody, and the ELISA. The IFA test is particularly useful for rapid diagnosis early in the course of infection, while the micro plaquereduction test is considered better for chronic infection. The CF test is considered relatively insensitive and is not recommended. Drawing and processing of blood from an animal suspected of LCMV infection should be done with care because of the likelihood of viremia.

The MAP test can be used in testing transplantable tumors and other biologic materials. The virus can also be identified by using the IFA test in tissues or cultures of isolated virus.

Control. The most practical method of control is to obtain mice only from colonies known to be free of LCMV and to maintain them in a barrier facility that excludes wild rodents. Biologic materials such as transplantable tumors should be pretested and shown to be free of the virus before experimental use. If LCMV infection is diagnosed, the entire stock should be destroyed and incinerated. Animal cages and other equipment should be autoclaved. Animal rooms should be fumigated either with formalin (40% formaldehyde in water, sprayed on all room surfaces at 36 ml/m³) or paraformaldehyde (11 g/m³vaporized in a high temperature silicone fluid at 96°C) and allowed to remain vacant for 7-10 days. Cesarean derivation of animal stocks is of no value because of transovarian or transuterine transmission of infection.

Interference with Research. LCMV infection is an important zoonotic infection that can cause serious disease and sometimes fatality in personnel. LCMV is a frequent contaminant of biologic materials, including transplantable tumors of mice, hamsters, and guinea pigs; tissue culture cell lines; virus stocks, including leukemia viruses, distemper virus, rabies virus, and mouse poliomyelitis virus; and Toxoplasma gondii sublines. LCMV infection has an inhibitory effect on tumor induction by polyomavirus, Rauscher virus, and mammary tumor virus. Acute infection has been reported to cause induction of natural killer cell activity, depression of both humoral and cellular immunity, delayed rejection of skin and tumor allografts, increased susceptibility to mousepox virus or Eperythrozoon coccoides infection, and increased susceptibility to bacterial endotoxin and x-irradiation. Abrogation of the naturally occurring insulin-dependent diabetes mellitus of BB strain rats has also been reported. Chronic infection has been shown to cause proliferation of virus-specific cytotoxic T lymphocytes.

Mammary Tumor Virus, Mouse

Agent. RNA virus, family Retroviridae. Four major variants have been identified: MMTV-S (standard; the Bittner virus), which is transmitted through the milk to nursing young and is highly oncogenic; MMTV-L (low oncogenic), which is transmitted through germ cells and is weakly oncogenic; MMTV-P (pregnancy-dependent), which is transmitted through both milk and germ cells and is highly oncogenic; MMTV-O (overlooked), which is considered an endogenous virus in the genome of most mice.

Animals Affected. Wild and laboratory mice.

Epizootiology. When infected, strains such as C3H, DBA/2, and A readily express MMTV-S, and the virus can be demonstrated in a variety of locations throughout the body, especially in mammary tissue and milk. Transmission of MMTV-S is by ingestion of infected milk, resulting in a high incidence of mammary tumors early in life (6-12 months) when the associated genetic and hormonal factors are also present.

Clinical. Tumors occur in any part of the body where mammary tissue is located. The lungs are the most common site for distant metastases.

Pathology. It is thought that the virus initially induces hyperplastic alveolar nodules that progress to neoplasia. The average latency period from infection to tumor expression is 6-9 months. Susceptibility to MMTV is genetically determined, and tumor development is enhanced by administration of estrogen to both males and females, forced breeding, and administration of carcinogens. Mammary tumors are usually circumscribed, round to nodular, gray to white masses located in the subcutaneous tissue. Ulcerations and hemorrhages are common in large tumors. Histologically, most are types A or B adenocarcinomas. Type A tumors are characterized by uniform acini lined by a single layer of cuboidal cells. Type B tumors are variable in the extent of differentiation but usually consist of irregular cords and sheets of cells. Types C, Y, L, and P adenocarcinomas; carcinomas with squamous cell differentiation; and carcinosarcomas occur less frequently. Other histologic types are rare. Mice of many strains develop humoral and cellular immune responses to MMTV, indicating that mice infected early in life are not immunologically tolerant.

Diagnosis. Pathologic diagnosis of mouse mammary tumors is based on histopathologic characteristics. Detection and characterization of the virus require test procedures normally available only in specialized viral oncology laboratories, including nucleic acid hybridization, immunologic assays for viral antigens, and bioassays for infectivity in different strains of mice.

Control. The most practical method of control is by selection of mouse strains without MMTV. Foster nursing of young on mouse strains that are free of the virus has been used to eliminate MMTV-S.

Interference with Research. MMTV infection can be a complicating factor in experimental carcinogenesis studies.

Minute Virus of Mice

Agent. DNA virus, family Parvoviridae, genus Parvovirus.

Animals Affected. Wild and laboratory mice.

Epizootiology. Wild mice serve as reservoir hosts. Enzootic infection is common in barrier-maintained and conventional breeding colonies of mice. Minute virus of mice (MVM) is highly contagious. In infected colonies, maternal antibodies are protective until the young are 6-8 weeks of age; however, most mice become infected and seroconvert by 3 months of age. Transmission occurs by direct contact and by urine and fecal contamination. Airborne and transplacental infection are not considered important.

Clinical. Natural infections are inapparent.

Pathology. There are no pathologic changes associated with natural infections.

Diagnosis. The ELISA and the IFA test are the most sensitive serologic tests. The HAI, CF, and neutralization tests are used to discriminate infections caused by MVM from those caused by Kilham rat virus or H-1 virus. MRL/MpJ and MRL/ MpJ-lpr/lpr mice frequently show false-positive HAI test results for MVM. Virus isolation can be done by using rat embryo tissue culture. The MAP test is commonly used for detection of MVM in transplantable tumors and other biologic materials.

Control. Infection can be eliminated from stocks of mice by cesarean derivation, but elimination of infected mice followed by replacement with MVM-free mice is often more practical. Strict adherence to barrier procedures is required to maintain the MVM-free state. Wild mice must be excluded. Transplantable tumors, virus stocks, and other biologic materials should be monitored before admission to a facility.

Interference with Research. MVM is a frequent contaminant of mouse leukemia virus preparations, transplantable tumors, hybridomas, and cell lines. Evidence that MVM can interfere with research has come from studies of MVM(i), a single variant of the virus that may or may not occur as a natural infection in contemporary mice. MVM(i) grows lytically in cytotoxic T-lymphocyte clones, abrogates cytotoxic T-lymphocyte responses, suppresses T-lymphocyte mitogenic responses, and suppresses T-helper-dependent B-lymphocyte responses in vitro. The intramuscular inoculation of MVM(p) into mice suppresses the growth of Ehrlich ascites tumor cells given intraperitoneally.

Mycoplasma arthritidis

Agent. Gram-negative bacterium, family Mycoplasmataceae.

Animals Affected. Rats and mice.

Epizootiology. M. arthritidis occurs as a common subclinical infection in rats and mice, including cesarean-derived, barrier-maintained stocks.

Clinical. The infection is usually subclinical; disease caused by this agent is extremely rare.

Pathology. There are no pathologic changes associated with subclinical infections.

Diagnosis. The ELISA should be used for screening; immunoblot on positive sera can be used to discriminate between species of Mycoplasma. Isolation of M. arthritidis from animals with subclinical infection requires culture of tissue homogenates from multiple organ sites, which is not practical in most instances. In the rare event that clinical arthritis occurs, the organism should be cultured from joint exudates.

Control. Definitive information is not available.

Interference with Research. Infection can cause spontaneous polyarthritis in rats. Subclinical infections can be activated to complicate experimentally induced arthritis in rats. M. arthritidis can contaminate transplantable tumors of rats, causing arthritis and/or abscesses at the injection site in recipients. Experimental infections of rodents with M. arthritidis can be complicated by preexisting latent infection with this organism. M. arthritidis is a frequent contaminant of rodent cell cultures.

Mycoplasma pulmonis

Agent. Gram-negative bacterium, family Mycoplasmataceae.

Animals Affected. Rats and mice. The organism is occasionally isolated from wild rats (Rattus norvegicus), cotton rats (Sigmodon hispidus hispidus), rabbits, Syrian hamsters, and guinea pigs.

Epizootiology. Infection and disease are common in conventionally reared rats and mice. Subclinical infection occurs in some cesarean-derived, barrier-maintained stocks. Transmission is thought to be by the intrauterine route and by aerosol between cagemates, including from dam to offspring and between adjacent cages.

Clinical. Infections are usually subclinical. Signs of murine respiratory mycoplasmosis (MRM), the disease caused by M. pulmonis, are nonspecific but can include rales, polypnea, weight loss, hunched posture, ruffled coat, inactivity, and ''head tilt," in both rats and mice; "snuffling" and accumulation of porphyrin pigment around the eyes and external nares in rats; and "chattering" in mice. Athymic (nu/nu) mice are no more susceptible to MRM than are immunocompetent mice.

Pathology. M. pulmonis is an extracellular parasite that preferentially colonizes the luminal surface of respiratory epithelium. Organisms and lesions, if present, tend to decrease from proximal to distal airways. Usually, the organism is a commensal. Intracage ammonia concentrations of 19 lg/l of air or greater appear to exacerbate MRM by increasing the growth of M. pulmonis in the respiratory tract. Other influencing factors include concurrent infection with Sendai virus, sialodacryoadenitis virus or cilia-associated respiratory bacillus; administration of hexamethylphosphoramide or cyclophosphamide; a deficiency of vitamins A or E; inhalation of tobacco smoke; genetic susceptibility of the host (e.g., LEW are more susceptible than F344 rats; C3H/HeN are more susceptible than C57BL/6N mice); and, possibly, virulence of the M. pulmonis strain. Characteristic changes at any level in the respiratory tract include neutrophils in the airways, hyperplasia of the mucosal epithelium, and a lymphoid response in the submucosa. Lesions can be acute or chronic and include rhinitis, otitis media, laryngitis, tracheitis, bronchitis, bronchiectasis, pulmonary abscesses, and alveolitis. Pleuritis and emphysema are rare. Hyperplasia of bronchus-associated lymphoid tissue is characteristic in rats. Syncytial epithelial giant cells can occur in nasal and bronchial mucosa in mice. LEW rats show genital disease, characterized by purulent endometritis, pyometra, salpingitis, and perioophoritis. In mice humoral antibody is protective and can be passively transferred. Cellular immunity appears to be more important in rats than in mice.

Diagnosis. Cultural isolation can be achieved by using a medium that has been pretested and shown to support growth. The nasopharynx is probably the best single site from which to obtain a culture sample, but culturing samples from multiple sites increases the isolation rate. A battery of bacterial, viral, and histopathologic procedures should be used to identify the responsible agent(s) and to exclude other possible causes or contributors. Efforts should be made to identify factors that exacerbate MRM. The ELISA is the method of choice for rodent health surveillance; it is more sensitive and cost effective than is culturing the organism. The ELISAs currently in use are only genus specific; therefore, immunoblot is used to differentiate between species of Mycoplasma. Detection of subclinical infection is often a major problem; ELISA seropositivity might occur only sporadically, the number of ELISA-positive animals might be very small, and seropositive animals might become negative again. The best results are obtained when only adults are tested (weanlings with subclinical infection usually are ELISA negative), sample size is increased, and testing is done repeatedly.

Control. Cesarean-derivation and barrier-maintenance programs appear to have reduced the prevalence of disease but may not have been equally successful in reducing the prevalence of infection. The major emphasis should be on selecting mycoplasma-free breeding stocks. This can be achieved by housing small groups of young adult breeders in plastic film isolators and testing them monthly using the ELISA until they are 12 months of age. Young animals from stocks found to be consistently negative can then be used to establish breeder production populations under barrier programs. Definitive information on eliminating M. pulmonis from clinically or subclinically infected stocks is lacking. Dams should be several months old and have been found repeatedly to be ELISA negative. Administration of antimicrobial agents might help to control clinical signs; however, such agents are not curative and can introduce variables if used in animals on experimental protocols.

Interference with Research. Morbidity and mortality caused by MRM can disrupt long-term studies. MRM alters ciliary function, cell kinetics, and immunity in the respiratory tract and changes the response to carcinogens. Infection in LEW rats delays the onset and reduces the severity of adjuvant arthritis, reduces the incidence of experimental collagen-induced arthritis, and reduces antibody response to collagen. Genital infection alters genital tract histology. In mice infection can activate natural killer cells, contaminate transplantable tumors, and cause arthritis in the recipients. Subclinical infection can be exacerbated by some experimental procedures (e.g., deficiencies of vitamin A or E, administration of hexamethylphosphoramide). M. pulmonis is a frequent contaminant of rodent cell cultures. Mycoplasmas produce lymphokine-like substances that are mitogenic for B and T lymphocytes in vitro.

Pasteurella pneumotropica

Agent. Gram-negative coccobacillus, family Pasteurellaceae.

Animals Affected. Mice, rats, hamsters, guinea pigs, and many others.

Epizootiology. P. pneumotropica can be isolated from up to 95% of healthy animals in some colonies. It can be isolated from many organs, including the respiratory tract, oral cavity, intestine, uterus, urinary bladder, skin, and conjunctiva. Transmission is probably by contact and fomites.

Clinical. Infections are usually subclinical. When clinical infections do occur, signs in mice include conjunctivitis, panophthalmitis, dacryoadenitis, subcutaneous and cervical abscesses, bulbourethral gland infections, uterine infections, and otitis media, while signs in rats include ophthalmitis, conjunctivitis, subcutaneous abscesses, and mastitis.

Pathology. P. pneumotropica is an opportunist that most frequently causes lesions of the skin and adnexal structures. Lesions are usually characterized by suppurative inflammation.

Diagnosis. Diagnosis must discriminate between P. pneumotropica infection and P. pneumotropica-induced disease and rule out other possible causative agents and disease processes. Pasteurella spp., Actinobacillus spp., Haemophilus spp., and Yersinia spp., which are commonly found in mice and rats, give similar reactions in many biochemical tests. Therefore, extensive biochemical testing is required to accurately identify these organisms. An ELISA for detection of serum antibody to P. pneumotropica has recently been developed.

Control. Cesarean derivation and maintenance in a gnotobiotic isolator may be necessary to exclude the organism completely. Antibiotic therapy has limited value.

Interference with Research. There have been no reports of interference with research results.

Pneumocystis carinii

Agent. Classification uncertain. Considered a fungus or a protozoan.

Animals Affected. Mice, rats, humans, and numerous other mammals.

Epizootiology. P. carinii is a ubiquitous organism of low virulence. It causes active pulmonary disease only in immunocompromised hosts. It is extremely prevalent as a persistent subclinical infection in mice and rats. Transmission is thought to be by inhalation of infective cysts expelled during exhalation or coughing.

Clinical Signs. Rats and mice show no clinical signs unless they are immunodeficient or immunosuppressed. Clinical signs include weight loss, cyanosis, rough hair coat, and dyspnea.

Pathology. In animals with active disease the lungs are enlarged, rubbery in consistency, plum colored, and heavier than normal. Histologically, alveolar septae are variably thickened, and there is a meager inflammatory response of lymphoid cells. Many alveoli are distended by homogeneous, foamy, eosinophilic material characteristic of P. carinii pneumonia.

Diagnosis. Definitive identification of P. carinii in active infection depends on the demonstration of cysts (characteristically containing eight sporozoites) and trophozoites. Cysts measure 5-7 Lgm in diameter and have thick walls that stain with methenamine silver, cresyl violet, periodic acid-Schiff, or toluidine blue. Giemsa stain is preferred for the demonstration of trophozoites and sporozoites in lung imprints. An IFA method also has been used. Acridine orange has been proposed for rapid screening of imprints; trophozoites stain yellow to orange; cyst walls do not stain. Persistent infections can be diagnosed by immunosuppressing some animals and then demonstrating the organisms in diseased lung tissue.

Control. Subclinical infection is probably very common in conventionally reared and pathogen-free colonies. Gnotobiotic methods are likely useful in excluding the infection but might not be completely effective because of possible vertical transmission.

Interference with Research. P. carinii can complicate long-term studies in which severely immunosuppressed animals are used. Athymic (nu/nu) and severe combined immunodeficient (scid/scid) mice can develop active infection.

Pneumonia Virus of Mice

Agent. RNA virus, family Paramyxoviridae, genus Pneumovirus.

Animals Affected. Mice, rats, and hamsters.

Epizootiology. Prevalence rates are approximately 50% in rat and hamster colonies and 20% in mouse colonies. Active infection in mice (and presumably in rats and hamsters) lasts about 9 days. Chronic or latent infections do not occur.

Transmission is exclusively horizontal via the respiratory tract, mainly by direct contact and aerosols. Fomites are probably not important in transmission.

Clinical Signs. Natural infections are subclinical, except in immunocompromised hosts. Chronic illness, emaciation, and death have been reported in infected athymic (nu/nu) mice.

Pathology. No pathologic lesions have been associated with natural infections in immunocompetent hosts. Chronic pneumonia has been reported to occur in naturally infected athymic mice.

Diagnosis. The ELISA is the most sensitive method for routine monitoring. The HAI test is also reliable, although occasionally it gives false-positive results. The CF test is useful for detecting recent PVM infections. The MAP test is useful for detecting the virus in biologic specimens. The virus can be isolated by using primary hamster kidney, BHK-21, Vero, or hamster embryo cells.

Control. Cesarean derivation and barrier maintenance are effective methods of controlling infection.

Interference with Research. There have been no reports of interference with research results.

Polyomavirus

Agent. DNA virus, family Papovaviridae, genus Polyomavirus.

Animals Affected. Wild and laboratory mice.

Epizootiology. Polyomavirus is very rare in mice from commercial barrier breeding facilities in the United States. The virus is highly contagious and is shed in large quantities in saliva, urine, and feces of infected mice. In persistently infected dams, the titer of virus in the kidney increases during late pregnancy. The virus has a propensity for airborne dissemination and intranasal infection. Contaminated feed and bedding can also be important sources of infection.

Clinical. Natural infections are usually inapparent. Athymic (nu/nu) mice given heterotransplants of human tumors contaminated with the virus have been reported to develop a syndrome characterized by wasting and paralysis of the rear legs and tail.

Pathology. Morphologic lesions, including polyomavirus-induced tumors, are usually not found in naturally infected mice.

Diagnosis. The ELISA and HAI test are commonly used in routine health monitoring. The MAP test can be used for screening tumor lines and other biologic materials. Virus isolation using mouse embryo tissue culture can be useful in selected situations.

Control. Cesarean derivation and barrier maintenance are usually effective in eliminating the virus because transplacental transmission does not occur. Strict isolation from polyomavirus-infected stocks and exclusion of wild mice from animal facilities are essential for preventing infection. Laminar-flow units and filter-top cages are helpful in reducing the spread of infection in laboratories in which the agent is used experimentally.

Interference with Research. Polyomavirus can complicate research by contaminating tumor lines, stocks of other viruses, and other biologic materials that are passaged in mice. Polyomavirus-contaminated tumors can cause paralysis and wasting in athymic (nu/nu) mice.

Pseudomonas aeruginosa

Agent. Gram-negative bacterium, family Pseudomonadaceae.

Animals Affected. Mice, rats, humans, and numerous other species.

Epizootiology. P. aeruginosa is ubiquitous, occurring widely in soil, water, sewage, and air. It is widely distributed in conventional stocks of rodents and is transmitted by fomites (e.g., contaminated food, bedding, or water) or by contact with infected humans or rodents.

Clinical. The organism is sometimes part of the normal flora in the digestive tract, and clinical signs are not present. Fulminating septicemia, resulting in death with few clinical signs, can occur in immunosuppressed animals. There are a few reports of "circling" or "rolling" in mice associated with otitis media and interna caused by this organism.

Pathology. Gross and histopathologic lesions are nonspecific. Occasionally there is suppurative otitis media with extension into the inner ears and to the adjacent meninges or brain. Animals subjected to severe immunosuppression (e.g., whole-body irradiation or cyclophosphamide administration) can develop fulminant septicemia with hemorrhage and multifocal necrosis in multiple organs.

Diagnosis. Diagnosis of P. aeruginosa infection is made by isolation and identification of the organism and exclusion of other possible causes of disease. In animals that have been immunosuppressed, septicemia should be demonstrated by culture of the organism.

Control. Control is only necessary for immunosuppressed rodents. Cesarean derivation followed by maintenance under gnotobiotic conditions completely eliminates the organism. P. aeruginosa can be eliminated from animal facilities by rigorous sanitation measures coupled with acidification and/or hyperchlorination of the water.

Interference with Research. Indigenous infections are of little importance except when the research involves immunosuppressed animals. Mice and rats naturally infected with P. aeruginosa typically die earlier than do noninfected controls when exposed to lethal doses of whole-body irradiation, cyclophosphamide, cortisone, or other immunosuppressants.

Reovirus-3

Agent. RNA virus, family Reoviridae, genus Reovirus.

Animals Affected. Mice, rats, hamsters, guinea pigs, and others.

Epizootiology. Reovirus-3 is prevalent in contemporary rodents. Transmission is by the fecal-oral route and probably by aerosol. Infected fomites may be important because reoviruses are relatively resistant to environmental conditions.

Clinical. Natural infections are subclinical.

Pathology. There are no pathologic changes associated with natural infections.

Diagnosis. The ELISA is the most sensitive method. The CF test is not reovirus type specific, and the HAI test is prone to give false-positive results for reovirus-3. Virus isolations can be performed using L cells or embryonic kidney cells. Transplantable tumors and cell lines can be screened for reoviruses by using tissue culture methods or the MAP test.

Control. Cesarean derivation and barrier maintenance appear to be effective methods of control.

Interference with Research. Reovirus-3 is an occasional contaminant of and may interfere with research involving transplantable tumors and cell lines.

Rotavirus, Mouse

Agent. RNA virus, family Reoviridae, genus Rotavirus, group A.

Animals Affected. Mice.

Epizootiology. Mouse rotavirus is thought to be widely prevalent, but this has not been documented for contemporary mouse stocks. Transmission is by airborne infection in which contaminated dust and bedding from adjacent cages probably play key roles. Mice are most susceptible to infection from birth to about 17 days of age. Infected neonates shed high concentrations of virus in the feces from about 2 to 8-10 days postinfection. Transient viremia and viruria can occur. Mice infected after about 17 days of age shed lower concentrations of virus in the feces for 2-4 days. It is not known whether there is persistent infection or whether very low concentrations of virus are shed in the feces beyond these time points. There is no evidence for transplacental transmission.

Clinical. Susceptibility to disease is age dependent, being greatest from 4 to 17 days of age. Infection in adults is subclinical. Diarrhea during the first 2 weeks of life is the only consistent sign of disease. Watery, yellow stools usually begin around 48 hours postinfection and persist for about 1 week. Varying amounts of stool accumulate around the anus and base of the tail, soiling the coats of neonates and their dams. Affected neonates may appear lethargic and have distended abdomens. Usually there is no mortality.

Pathology. The infection progresses from the proximal to distal end of the intestine, involving the duodenum,jejunum, ileum, and colon. The virus selectively infects epithelial cytoplasm and destroys cells near the tips of the villi in the small intestine, resulting in mild villous atrophy. Cytoplasmic vacuoles of varying size occur in the mucosal epithelium.

Diagnosis. Diagnosis is made by serologic testing using the CF test, radioimmunoassay, IFA test, ELISA, or other methods; by demonstration of rotaviral antigen lesions in the small intestine; or by isolation of the virus using trypsinized primary monkey kidney cells.

Control. Cesarean derivation and exclusion by barrier maintenance are the traditional methods of control. However, it is more practical to use such methods as isolation and quarantine of individual breeding pairs with subsequent selection of seronegative progeny for breeding. The use of filter-top cage systems can be beneficial in controlling the transmission of infection among subpopulations housed in the same room.

Interference with Research. Infection can alter research results in studies using infant mice. Protein-calorie deprivation of nursing dams increases the severity of diarrhea, increases mortality, and reduces the weight gains of MRV-infected infant pups. Folic acid deficiency also increases the severity of diarrheal disease.

Rotavirus-infected infant mice show increased mortality when challenged with enterotoxigenic Escherichia coli.

Salmonella enteritidis

Agent. Gram-negative bacterium, family Enterobacteriaceae, tribe Salmonellae. There are more than 1,500 serotypes of Salmonella enteritidis.

Animals Affected. Mice, rats, humans, and many others.

Epizootiology. Prevalence in laboratory rodents is unknown, but there is evidence that subclinical infections caused by weakly virulent strains are common in the United States. Infections are acquired primarily by ingestion, usually from contaminated food, water, or bedding. After initial colony infection, about 5% of the animals become asymptomatic, chronic carriers and shed organisms in the feces for many months.

Clinical. Most infections in mice are subclinical. In clinical outbreaks, nonspecific signs, including ruffled fur, hunched posture, reduced activity, weight loss, conjunctivitis, and variable mortality, follow an incubation period of 2-6 days. Diarrhea occurs in only about 20% of animals. Enzootically infected breeding colonies can have alternating periods of inapparent infection and overt clinical disease. Litter sizes and birth weights can be reduced. Clinical salmonellosis in rats is extremely rare. Virulence and dose of the organism and the host's age, strain, intestinal microflora, nutritional state, immune status, and intercurrent infections affect the expression of disease. C3H/HeN, C3H/St, C3H/Bi, CBA/Ca, BRVR, A/J, A/HeN, SWR/J, and DBA/2 mice are relatively resistant to S. enteritidis-induced disease, while BSVS, DBA/1, BALB/c, C57BL/6, C3H/HeJ, and CBA/N mice are relatively susceptible. Three distinct genetic loci affect susceptibility: Ity (immunity to S. typhimurium), Lps (lipopolysaccharide response), and xid (X-linked immune deficiency). Weanling mice are more susceptible than adults. Susceptibility to clinical disease is increased by food and water deprivation, nutritional iron deficiency in rats, nutritional iron overload in mice, pretreatment with sodium bicarbonate by gavage, and administration of morphine sulfate to slow gastrointestinal motility.

Pathology. Gross lesions are extremely variable, depending on the stage of disease. Animals that die of acute infection may have only hyperemia and congestion of visceral organs. Animals that survive a week or longer often appear emaciated, have hyperemia and thickening of the ileal and cecal walls, an empty or fluid-filled large intestine, multiple white or yellow foci in the liver, splenomegaly, enlarged mesenteric lymph nodes, and fibrinous exudate in the peritoneal cavity. Chronic carriers usually do not have gross lesions. The predominant microscopic lesions of salmonellosis are ileocecitis, mesenteric lymphadenitis, and multifocal inflammation in the liver and spleen, each varying in character depending on the stage of disease. There is multifocal to diffuse destruction of villous epithelium in the ileum, with blunting of villi and hyperplasia of crypt epithelium and purulent to pyogranulomatous inflammation in the lamina propria. Similar changes occur in the cecum, which is more severely affected in rats than in mice. Ulcerative cecitis, accompanied by severe pyogranulomatous inflammation in the lamina propria and purulent to chronic inflammation leading to atrophy and cyst formation in the paracecal lymph nodes, is characteristic of salmonellosis in rats. Multifocal purulent, pyogranulomatous, or granulomatous inflammation occurs in the mesenteric lymph nodes, liver, and spleen. So-called cell-fragment thrombi commonly occur in liver and spleen in which necrotic foci break into venous channels. Peritonitis is commonly caused by extension of the infection through the capsule of the liver, lymph nodes, or spleen. Cholangitis and cholecystitis are seen infrequently. Pyogranulomatous inflammation occasionally occurs in other organs such as the lungs.

Diagnosis. S. enteritidis is diagnosed by cultural isolation and serologic typing of isolates. It is usually best to culture the liver, spleen, intestine, feces, and blood. Characteristic histopathologic lesions help to rule out diseases with similar gross lesions (e.g., mousepox, Tyzzer's disease, and streptobacillosis in mice). Carriers must be detected by cultural isolation of the organism because there is no satisfactory serologic method for testing suspected carriers.

Control. Affected animals pose a zoonotic risk to personnel, are a source of infection for other animals, and are unsuitable for research. The usual method of control is to destroy the entire population and replace it with animals from a pathogen-free source. For extremely valuable stocks, cesarean derivations can be attempted. Prevention is by barrier maintenance, avoidance of Salmonella-contaminated food and water, and exclusion of infected animals and wild rodents from the animal facility. Regular monitoring is necessary.

Interference with Research. Salmonella-infected mice can have a nonspecific resistance to challenge with other intracellular parasites such as Listeria monocytogenes. Prior immunization of mice with viable S. enteritidis has resulted in the suppression of growth of transplantable tumors. Concurrent infections of S. enteritidis and Plasmodium berghei in mice have resulted in higher mortality than infection by either agent alone. S. enteritidis infection has caused reduced blood glucose and hepatic enzyme levels. Mice orally infected with S. enteritidis have reduced intestinal enzyme activities. Susceptibility to infection is increased by some experimental procedures.

Sendai Virus

Agent. RNA virus, family Paramyxoviridae, genus Paramyxovirus.

Animals Affected. Mice, rats, hamsters, and possibly guinea pigs.

Epizootiology. Sendai virus (SV) is extremely contagious. Prevalence is considered high in colonies of laboratory mice and rats worldwide. Natural infection occurs via the respiratory tract. Transmission is by direct contact and fomites and is highly efficient. Viral replication is thought to be limited to the respiratory tract and occurs for only about 1 week postinfection.

Clinical. Natural SV infection in rats is usually subclinical. In pregnant rats, the infection can cause fetal resorptions, retarded embryonic development, and mortality of neonates. Susceptibility to SV-induced disease in mice is dependent on the strain or stock. Those that are the most susceptible include 129/ReJ, 129/J, DBA/1J, DBA/2J, and S-nu/nu (Swiss carrying the mutation nude). Strains of intermediate susceptibility include A/HeJ, A/J, SWR/J, C57BL/10Sn, and BALB/c. The most resistant strains and stocks include SJL/J, RF/J, C57BL/6J, and S. The mode of inheritance and mechanisms of host resistance are poorly understood. Clinical disease caused by natural SV infection in mice falls into one of two patterns. Enzootic (subclinical) infection commonly occurs in breeding populations. Adults have active immunity due to prior infection, and newborn mice are passively protected by maternal antibody until around 4-8 weeks of age, when they become infected. Recovery is prompt and usually without morbidity or mortality. Epizootic (clinically apparent) infection occurs when a mouse population is first infected. Infection quickly spreads through the entire population. Signs are variable but may include chattering; mild respiratory distress; and prolonged gestation in adults, deaths in neonates and sucklings, and poor growth in weanling and young adults. Breeding colonies return to normal productivity in 2 months and thereafter maintain the enzootic pattern of infection. Epizootics of disease that exceed these general patterns in clinical severity should arouse suspicion of complication by other agent(s), particularly Mycoplasma pulmonis and cilia-associated respiratory bacillus.

Pathology. There are few gross lesions in uncomplicated SV infections. The lungs can appear focally reddened or atelectatic, and serous fluid can be visible in the pleural and pericardial cavities. The most severe lesions are seen in mice that are infected as sucklings or weanlings and in mice of the more susceptible strains. Severe necrotizing bronchitis and bronchiolitis often cause intense inflammatory injury to terminal bronchioles, resulting in scarring with severe distortion of the smaller airways and formation of polypoid outgrowths into bronchiole lumens. There is also pronounced hyperplasia of airway epithelium resulting in peribronchiolar adenomatous hyperplasia that can persist throughout life. In aged mice the air spaces in these lesions are often filled with mucus, large macrophages, and cellular debris. There can be large eosinophilic crystals in the air spaces, cytoplasm of the macrophages, and cells forming the adenomatoid structures. The terminal bronchioles of rats may be scarred and distorted but do not show the hyperplastic peribronchiolar changes seen in mice.

Athymic (nu/nu) mice develop chronic pneumonia similar to that in immunocompetent mice but have abundant intranuclear and intracytoplasmic inclusions in laryngeal, tracheal, bronchial, and bronchiolar epithelia, as well as in type I and II pneumocytes and alveolar macrophages. The virus persists for 10 weeks or longer. Athymic (rnu/rnu) rats also have increased susceptibility to SV and develop a similar chronic lung disease.

Diagnosis. The ELISA is the test of choice for routine serologic monitoring. The ELISA also successfully detects anti-SV antibody in infected athymic (nu/nu) mice. An avidin-biotin-peroxidase-complex method has been used successfully for demonstrating SV antigen in histologic sections. Isolation of SV can be achieved by using BHK-21 or primary monkey kidney cell cultures or by inoculating the amniotic or allantoic sacs of 8- to 10-day-old embryonated hen's eggs. The MAP test can be used for determining contamination of transplantable tumors and other biologic materials.

Control. To prevent the introduction of infection, only animals known to be free of SV should be obtained, and the animals should be maintained under strict barrier conditions. In addition, all biologic materials, such as transplantable tumors, should be pretested and shown to be free of the virus. If SV infection is detected, prompt elimination of infected subpopulation(s) is essential to prevent spread of the infection to other rodents. A less effective alternative is to place the infected animals under strict quarantine, remove all young and pregnant females, suspend all breeding, and prevent the addition of other susceptible animals for a period of 6-8 weeks until the infection has run its course and the virus has been eliminated naturally. Cesarean derivation is effective but usually is not warranted. Vaccination might prove useful in some situations.

Interference with Research. Experimental SV infection alters the phagocytic function of pulmonary macrophages. Concurrent SV and M. pulmonis infections are synergistic in mice, causing disease of far greater severity than that caused by either agent alone. It has been reported (but not confirmed) that infected mice have deficiencies in T- and B-cell function that persist throughout life, but most of the evidence indicates that such deficiencies are transient, lasting only a few weeks. SV infection inhibits in vitro mitogenesis of lymphocytes, increases natural killer cell-mediated cytotoxicity, and increases cytotoxic lymphocyte responses after in vivo stimulation with SV-coated syngeneic cells. Isograft rejection is altered and the neoplastic response to respiratory carcinogens can be increased or decreased. Wound healing is delayed. Cyclophosphamide increases the clinical and pathologic severity of SV infection. SV infection in rats alters the mitogenic responses of T cells, reduces the severity of adjuvant arthritis, and decreases antibody response to sheep erythrocytes. SV infection alters host responses to transplantable tumors.

Sialodacryoadenitis Virus

Agent. RNA virus, family Coronaviridae, genus Coronavirus.

Animals Affected. Rats. Mice are susceptible to experimental infection, but natural infection has not been reported for this species.

Epizootiology. Sialodacryoadenitis virus (SDAV) is one of the most common viruses in laboratory rats. It is highly contagious and transmitted by contact and aerosol. It is not transmitted vertically. LEW, WAG/Rij, and SHR rats are more susceptible than WI (Wistar), SD (Sprague-Dawley®), LE (Long Evans), and F344.

Clinical Signs. Enzootic disease: Adults are immune because of previous infection. Suckling rats have a mild, transient (1 week or less) conjunctivitis accompanied by blinking. Occasionally, exudate causes the eyelids to adhere together. Clinical signs usually disappear by weaning. Epizootic disease: Overt disease occurs in naive rat populations. There is a sudden high incidence of overt disease. Signs include cervical edema; sneezing; photophobia; serous to seropurulent, often porphyrin-stained nasal and ocular discharge; corneal ulceration; and keratoconus. There is high morbidity but no mortality. Most clinical signs disappear in a week, but the eyes might be more prominent than normal for 1-2 weeks because of inflammation of retroorbital tissues.

Pathology. SDAV has a positive tropism for serous or mixed serous-mucous tubuloalveolar glands. The submaxillary and parotid salivary, exorbital lacrimal, Harderian, and intraorbital lacrimal glands are the major target organs. There are also mild changes in the cervical lymph nodes, thymus, and respiratory tract. Characteristically, by 5 days postinfection, there is diffuse necrosis of alveolar and ductal epithelium in the salivary and lacrimal glands, and polymorphonuclear leukocytes quickly infiltrate the necrotic debris and interstitium accompanied by interstitial edema. The ductal epithelium is rapidly repaired, becoming hyperplastic and squamous in appearance by 10 days postinfection. Intranuclear inclusions are occasionally observed. Complete restoration of normal glandular architecture requires about 30 days. Eye lesions include interstitial keratitis, corneal ulceration, keratoconus, synechia, hypopyon, hyphema, and conjunctivitis. Sequelae of infection can include megaloglobus with lenticular and retinal degeneration. Thymic lesions are limited to focal necrosis of the cortex and medulla with some widening of the interlobular septae. Focal necrosis and lymphoid hyperplasia occur in cervical lymph nodes.

Diagnosis. The ELISA and the IFA test are more sensitive than the CF test. Presumptive diagnosis often can be based on characteristic histologic changes in Harderian, submaxillary, and parotid glands. Lesions can be bilateral or unilateral and are frequently found in animals with negative serologic tests for coronavirus antibody. The virus can be isolated by culture methods using primary rat kidney cells orby intracerebral inoculation of neonatal mice. The virus can be demonstrated in affected tissues by immunofluorescence for only about 7 days postinoculation.

Control. Control requires very strict adherence to preventative measures, including procurement only of rats known to be free of SDAV and adherence to strict barrier housing procedures. Prompt elimination of infected subpopulation(s) is essential to prevent spread of infection to other rodents. A less effective alternative is to place infected animals under strict quarantine, remove all young and pregnant females, suspend all breeding, and discontinue adding other susceptible animals for a period of 6-8 weeks until the infection has run its course and the virus has been eliminated naturally.

Interference with Research. The virus can seriously complicate studies involving the eyes, salivary glands, lacrimal glands, or respiratory tract. It is reported to reduce reproductive rate in breeding populations and slow growth rate of young rats. It inhibits phagocytosis and interleukin-1 production by pulmonary macrophages. SDAV infection exacerbates concurrent Mycoplasma pulmonis infection.

Staphylococcus aureus

Agent. Gram-positive bacterium, family Micrococcaceae.

Animals Affected. Mice, rats, humans, and many others.

Epizootiology. S. aureus commonly colonizes the nasopharynx, lower digestive tract, fur, and skin. It is readily cultured from cages, room surfaces, and personnel. The epizootiology of pathogenic types in animals is poorly understood. Human carriers might be an important source of infection for rodent colonies and vice versa. Many rodent colonies have infection without overt disease. Pathogenesis is probably dependent on many factors, including phage type(s), traumatic injuries of skin or mucosal surfaces, host factors, and sanitation.

Clinical. Rats: Ulcerative dermatitis with intensely pruritic, moist eczematous lesions (usually 1-2 cm in diameter) occurs on the lateral surfaces of the shoulders and neck. Lesions appear to be initiated or aggravated by scratching. Mice: Ulcerative dermatitis with moist eczematous lesions occurs on the face, neck, ears, and forelegs. Multiple abscesses and botryomycotic granulomas can develop in deeper tissues of the face, including the orbital tissues, facial muscles, peridontium, and mandibles. Purulent lesions of varying size occur commonly around the eyes and on the face of athymic (nu/nu) mice. Abscesses also occur in preputial glands, which become firm and enlarged to a few millimeters in diameter. The highest incidence of preputial gland abscesses is in strain C3H/HeN. In strain C57BL/6N, the organism has been associated with a syndrome involving self-mutilation of the penis.

Pathology. Suppurative inflammation is a hallmark of tissue invasion by S. aureus. In ulcerative dermatitis, there is destruction of the epidermis, and the underlying dermis contains pustules; abscesses; and, eventually, chronic or granulomatous inflammation. Large numbers of organisms are usually present and can be demonstrated readily in Gram-stained sections or imprints. Preputial abscesses in C3H/HeN mice apparently are caused by ascending infection from the ducts of the preputial glands.

Diagnosis. Diagnosis depends on the isolation and identification of S. aureus and exclusion of other agents (e.g., dermatophytes and mites) as possible causes of the lesions.

Control. The best methods of control are improved sanitation, frequent sterilization of cages and other equipment, elimination of equipment that could cause skin injury, and reduction in the number of animals per cage.

Interference with Research. S. aureus alters host immune responses (e.g., activates suppressor B cells). Rats maintained on prolonged immunosuppression with corticosteroids can develop S. aureus-induced renal abscesses.

Streptobacillus moniliformis

Agent. Gram-negative bacterium; taxonomy uncertain.

Animals Affected. Rats. Mice, guinea pigs, humans, and others can contract the infection from rats.

Epizootiology. S. moniliformis is a commensal of the nasopharynx in wild and conventionally reared laboratory rats. It has not been reported in cesarean-derived, barrier-maintained rats or mice. Epizootic disease is most likely to occur in mice housed near infected rats. Transmission is by rat bites, aerosols, and fomites.

Clinical. In rats the infection is subclinical. The organism can be isolated from the nasopharynx, middle ear, respiratory tract, and subcutaneous abscesses. In mice, early signs include conjunctivitis, photophobia, cyanosis, diarrhea, anemia, hemoglobinuria, emaciation, and high mortality. Septicemia clears in survivors in a few weeks, but infection persists around the joints for about 6 months. During this chronic phase of infection, there can be diffuse swelling and reddening of limbs or tail, with the development of chronic arthritis, deformity and ankylosis, or amputation (ectromelia). Spinal lesions, accompanied by posterior paralysis, kyphosis, and priapism, can occur. Pregnant females can abort or produce stillborn young.

Pathology. In mice, early lesions are associated with septicemia, including focal necrosis of the spleen and liver, splenomegaly, and lymphadenopathy. Subsequent lesions are primarily those of chronic arthritis in various stages of development and severity.

Diagnosis. Diagnosis depends on cultural isolation and identification of the organism. Differential diagnosis should distinguish between S. moniliformis-induced disease and mousepox or bacterial septicemias caused by other organisms (e.g., Corynebacterium kutscheri, Salmonella enteritidis).

Control. Cesarean derivation, barrier maintenance, and regular monitoring for rodent pathogens by a comprehensive health surveillance program are the best methods of control. Mice should not be housed in the same room as rats that have not been monitored for S. moniliformis infection.

Interference with Research. There have been no reports of interference with the results of research in which rats were used. S. moniliformis can cause high mortality in mice and is a serious zoonotic infection in humans.^*

Streptococcus pneumoniae

Agent. Gram-positive bacterium, family Streptoccaceae.

Animals Affected. Only subclinical infection has been reported in mice. Disease has been reported occasionally in rats, guinea pigs, and monkeys. Humans are the main natural hosts.

Epizootiology. Transmission is mainly by aerosol.

Clinical Signs. Signs include dyspnea, weight loss, hunched posture, snuffling respiratory sounds, and abdominal breathing. Clinical onset can be sudden, and young rats are affected most often.

Pathology. Predominant lesions in rats are suppurative rhinitis and otitis media. The disease often extends into distal airways, causing acute tracheitis and fibrinous lobar pneumonia, and into organs adjacent to the lungs, causing fibrinous pleuritis or empyema, fibrinous pericarditis, and/or acute mediastinitis. Lesions associated with severe bacteremia include suppurative arthritis, meningitis, hepatitis, splenitis, peritonitis, and orchitis. Splenic and testicular infarcts can occur. Abdominal lesions are frequently the primary cause of death.

Diagnosis. Diagnosis is made by isolating the organism from sites with characteristic lesions and excluding other possible causes and contributors to the disease.

Control. Cesarean derivation and barrier maintenance are extremely effective methods of control. It might be helpful for personnel to wear masks because of the high prevalence of the infection in humans.

Interference with Research. S. pneumoniae-induced septicemia alters hepatic metabolism, serum biochemistries, and thyroid function. Studies involving the rat respiratory tract can be jeopardized.

Theiler's Murine Encephalomyelitis Virus

Agent. RNA virus, family Picornaviridae, genus Enterovirus.

Animals Affected. Laboratory mice and rats. The infection has not been reported in wild mice or rats.

Epizootiology. The prevalence of Theiler's murine encephalomyelitis virus (TMEV) in mice is generally thought to be very low in barrier breeding colonies in the United States. Prevalence in laboratory rats is unknown. In naturally infected mice, there is a low titer of virus in intestinal mucosa; intestinal contents; feces: and, less frequently, mesenteric lymph nodes. Virus shedding in the feces has been documented to occur as long as 154 days postinfection. Transmission is by the fecal-oral route. Transplacental infection does not occur.

Clinical. Natural infections in mice are usually inapparent and, presumably, are caused by less virulent, wild-type strains of TMEV resembling Theiler's original (TO) strain of virus. Clinical disease appears at a rate of only 1 in 4,000-10,000 infected animals. Affected mice may have flaccid paralysis of one or both rear legs. There is little or no mortality. Signs of infection with a highly virulent strain of TMEV in one natural outbreak included circling, rolling, hyperexcitability, convulsions, tremors, weakness or flaccid paralysis of the hind legs, and high mortality. Cinical signs of infection with the MHG strain of TMEV in rats included circling, incoordination, tremors, and torticollis.

Pathology. Natural disease in mice results from the rare occurrence of viremia, i.e., the dissemination of virus from the intestine to the spinal cord and brain. This occurs most frequently around 6-10 weeks of age. The predominant lesion is poliomyelitis, with necrosis and neuronophagia of anterior horn cells and nonsuppurative inflammation composed primarily of lymphocytes. Little if any secondary demyelination is seen in the natural disease. TMEV can be isolated from the lesions for at least 1 year.

Diagnosis. The ELISA is the method of choice for serologic screening. If the HAI test with GDVII antigen and human type O erythrocytes is used, it is essential to perform the test at 4°C to avoid false-positive results. The CF and serum neutralization tests might also be useful for some purposes, such comparison of the cross-reactivity of TMEV strains. The MAP test can be used for screening biologic materials. Definitive diagnosis usually is made by isolating the virus from the spinal cords or brains of mice with clinical disease, but it is also possible to isolate the virus from the intestinal contents of mice with asymptomatic infections.

Control. The most practical method of control is to obtain mice from breeding populations that have been shown serologically to be free of the infection, followed by barrier maintenance and regular testing to reconfirm TMEV-free status. TMEV infection has been eliminated from valuable mouse stocks by foster nursing infant mice on TMEV-free mice or rats. Cesarean derivation is also effective but usually is not warranted.

Interference with Research. Indigenous TMEV infections occasionally interfere with studies of other unrelated viruses in mice.

Thymic Virus, Mouse

Agent. Considered a herpesvirus because of its ultrastructural features and properties of heat and ether lability.

Animals Affected. Wild and laboratory mice.

Epizootiology. Wild mice apparently serve as reservoir hosts. Prevalence in laboratory mice is unknown; however, limited data suggest natural infections might be common. Mouse thymic virus (MTV) apparently occurs as a persistent subclinical infection in salivary glands, with virus shed in saliva. Horizontal transmission is most important, but vertical transmission cannot be ruled out.

Clinical Signs. Natural infections are subclinical.

Pathology. There are no pathologic changes associated with natural infections.

Diagnosis. The ELISA is the most sensitive serologic test, although the IFA and CF tests are also in use. However, these tests are only useful for screening adult mice; neonatally infected mice do not produce serum antibody. To detect MTV infection in neonatal mice, it is necessary to inoculate pathogen-free neonatal mice with salivary gland homogenate, saliva, or other material from the neonatal mice to be tested. If the test mice are infected with MTV, histologic examination of the thymuses, lymph nodes, and spleens of the pathogen-free mice 10-14 days postinoculation will disclose lymphoid necrosis and intranuclear inclusions. Virus isolation is impossible because no cell culture system is known to support its growth.

Control. No data are available.

Interference with Research. MTV infection might complicate experiments involving the passage of tissues in neonatal mice.

Footnotes

*: Signs of KHF in humans vary from mild to severe and include fever, headache, muscular pains, hemorrhages (cutaneous petechia or ecchymoses. hemoptysis, hematuria, hematemesis, melena), and proteinuria.
*: This virus was designated "H-1" by Toolan in 1961, and this is its official taxonomic name. In the United States, the virus is commonly called Toolan H-1 virus.
*: In humans the usual clinical manifestations are those of flu-like disease, with fever, headache, myalgia, nausea, vomiting, sore throat, and photophobia being the major symptoms. The following occur rarely: rash, alopecia, diarrhea, cough, arthritis, lymphadenopathy, orchitis, delirium, amnesia, meningitis.
*: In humans the incubation period is usually 3-10 days, followed by the abrupt onset of fever, chills, vomiting, headache, and myalgia. There is a maculopapular rash that is most pronounced on the extremities. Arthritis occurs in about two-thirds of cases, and other complications such as endocarditis and focal abscesses occur in some untreated cases.

Bookshelf ID: NBK235409

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National Research Council (US) Committee on Infectious Diseases of Mice and Rats. Companion Guide to Infectious Diseases of Mice and Rats. Washington (DC): National Academies Press (US); 1991. BACTERIA, FUNGI, AND VIRUSES.
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Adenoviruses
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Bacillus piliformis
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Cilia-Associated Respiratory Bacillus
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Citrobacterfreundii Biotype 4280
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Corynebacterium kutscheri
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Cytomegalovirus, Mouse
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Ectromelia Virus
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Encephalitozoon cuniculi
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Hantaviruses
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Hepatitis Virus, Mouse
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H-1 Virus
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Kilham Rat Virus
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Lactic Dehydrogenase-Elevating Virus
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Leukemia Viruses, Murine
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Lymphocytic Choriomeningitis Virus
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Mammary Tumor Virus, Mouse
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Minute Virus of Mice
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Mycoplasma arthritidis
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Mycoplasma pulmonis
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Pasteurella pneumotropica
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Pneumocystis carinii
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Pneumonia Virus of Mice
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Polyomavirus
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Pseudomonas aeruginosa
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Reovirus-3
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Rotavirus, Mouse
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Salmonella enteritidis
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Sendai Virus
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Sialodacryoadenitis Virus
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Staphylococcus aureus
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Streptobacillus moniliformis
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Streptococcus pneumoniae
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Theiler's Murine Encephalomyelitis Virus
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Thymic Virus, Mouse
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Companion Guide to Infectious Diseases of Mice and Rats.

BACTERIA, FUNGI, AND VIRUSES

Adenoviruses

Suggested Reading

Bacillus piliformis

Suggested Reading

Cilia-Associated Respiratory Bacillus

Suggested Reading

Citrobacterfreundii Biotype 4280

Suggested Reading

Corynebacterium kutscheri

Suggested Reading

Cytomegalovirus, Mouse

Suggested Reading

Ectromelia Virus

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Encephalitozoon cuniculi

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Hantaviruses

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Hepatitis Virus, Mouse

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H-1 Virus*

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Kilham Rat Virus

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Lactic Dehydrogenase-Elevating Virus

Suggested Reading

Leukemia Viruses, Murine

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Lymphocytic Choriomeningitis Virus

Suggested Reading

Mammary Tumor Virus, Mouse

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Minute Virus of Mice

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Mycoplasma arthritidis

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Mycoplasma pulmonis

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Pasteurella pneumotropica

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Pneumocystis carinii

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Pneumonia Virus of Mice

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Polyomavirus

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Pseudomonas aeruginosa

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Reovirus-3

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Rotavirus, Mouse

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Salmonella enteritidis

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Sendai Virus

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Sialodacryoadenitis Virus

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Staphylococcus aureus

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Streptobacillus moniliformis

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Streptococcus pneumoniae

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Theiler's Murine Encephalomyelitis Virus

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Thymic Virus, Mouse

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H-1 Virus^*