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Brogden KA, Guthmiller JM, editors. Polymicrobial Diseases. Washington (DC): ASM Press; 2002.

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Polymicrobial Diseases.

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Chapter 12Respiratory Viruses and Bacteria in Cattle

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Author Information

,1 ,2 and 1.

1 Department of Pathobiology, Ontario Veterinary College, University of Guelph, Guelph, Ontario N1G 2W1, Canada.
2 Biocor Animal Health, 2720 North 84th St, Omaha, NE 68134.

Bovine respiratory disease is the principal source of economic loss for the North American beef industry and a significant health problem in the dairy industry as well (151). The pathogenesis typically involves some combination of predisposing stress which compromises respiratory defense mechanisms and coincidental primary infection with one or more respiratory viruses. Viral infection and the host's response to it further compromise defense and facilitate colonization of deeper pulmonary tissues by bacteria normally carried in the nasopharynx, especially members of the family Pasteurellaceae (54). Often called pneumonic pasteurellosis, this disease syndrome has a multifactorial nature that is better captured in its designation as the bovine respiratory disease complex (BRD) (47). Catastrophic outbreaks or "wrecks" involving large numbers of animals typically follow a week to 10 days after shipment of calves to feedlots, hence the alternative name "shipping fever," but isolated cases in home-reared calves and dairy animals are also recognized. Clinical diagnosis, based on the presence of lethargy or depression, reduced feed intake, fever, increased respiratory rate, and dyspnea, with or without nasal discharge, is often made without attempt to identify the offending viruses or bacteria, leaving the diagnosis as undifferentiated bovine respiratory disease (UBRD). Treatment with broad-spectrum antibiotics may assist recovery in many animals, though feed conversion, weight gain, and the resulting economic return can be seriously compromised in those that recover. Prevention would be the preferred intervention, and many vaccines targeting the various bacteria and viruses implicated in BRD have been developed over the last 70 or more years. Those developed in the past decade or so have shown enhanced efficacy but at best protect only 75% of vaccinated animals and provide no protection in outbreaks where the causative organisms are not those most commonly targeted by vaccines. Thus, the search to identify pathogenic mechanisms and virulence factors for both viral and bacterial contributors to disease continues, and as a result the importance of certain defense mechanisms in protection of the respiratory tract is being investigated.

The viruses most frequently associated with BRD include infectious bovine rhinotracheitis virus, a type 1 bovine herpesvirus (BHV1), parainfluenza virus type 3 (PI3), bovine respiratory syncytial virus (BRSV), and bovine viral diarrhea virus (BVDV). Other viruses which may be involved and could be underestimated are bovine adenovirus and bovine coronavirus (BCV). In addition, there are several viruses which are occasionally implicated by serological evidence but for which no clear or consistent association has been made: bovine calicivirus, bovine parvovirus, BHV4, bovine reovirus, bovine enterovirus, bovine rhinovirus, and malignant catarrhal fever virus.

Secondary bacterial pneumonia is typically attributed to members of the family Pasteurellaceae, including Mannheimia haemolytica (formerly Pasteurella haemolytica), Pasteurella multocida, and Haemophilus somnus.

Other bacteria that have been isolated with some frequency are mycoplasmas, especially Ureaplasma diversum, Mycoplasma dispar, Mycoplasma bovis, and Mycoplasma bovirhinis.

Chlamydia spp. have been recovered from pneumonic lungs of cattle with BRD, coincidentally with Pasteurellaceae and mycoplasmas (108). Although chlamydiae alone do cause primary respiratory disease, their role in UBRD is uncertain and their coincidental isolation may be merely that.

Pasteurellaceae are commensal inhabitants of the upper respiratory tract in cattle, from which they are normally inhaled in small numbers and rapidly cleared by the mucociliary escalator of the trachea and large bronchi (53). This clearance may be impaired when the animals are stressed by changes in weather, change in feed or housing, or transport. Endogenous release of stress hormones has been shown to increase mucus production and decrease ciliary activity, impair recruitment of neutrophils into pulmonary tissue, and reduce the phagocytic activity of resident alveolar macrophages. In addition, the numbers of bacteria isolated from the nasopharynx and tonsillar regions increase during transport or similarly stressful changes in environment (53). While the mechanism for this enhanced bacterial colonization is not known, the result is an increase in the numbers of inhaled bacteria that is coincident with reduced nonspecific defenses. Furthermore, one direct result of the mixing of calves from different farms of origin, as occurs in assembly of the feedlot herd, is the transmission of respiratory viruses from apparently healthy carriers to their naive pen-mates. Many of those viruses, which are known to predispose animals for development of pneumonic pasteurellosis, have direct effects on bacterial clearance mechanisms in the lung, affecting especially the ability of virus-infected alveolar macrophages to take up and kill inhaled bacteria (71). In addition, the antigenspecific immune response to the virus results in killing of virus-infected epithelial cells and macrophages, further compromising clearance and rendering the host extremely vulnerable. The importance of the antiviral immune response in facilitating bacterial pneumonia is clearly demonstrated in experimental models of bovine pneumonia in which the interval between viral challenge and bacterial challenge is critical for production of disease and corresponds directly to the point when antiviral antibodies are first detected in serum (64). Pneumonia can be induced experimentally with bacteria alone but only by direct pulmonary inoculation (intrabronchial instillation or transthoracic injection) using larger numbers of bacteria than are needed for aerosol or intranasal challenge following viral prechallenge (87).

Bovine Respiratory Viruses


BHV1 infection has been associated with a variety of clinical syndromes resulting from infection of the genital, respiratory, or digestive tract: abortion, encephalitis, mastitis, and tracheitis (130). Clinical manifestations reflect both the route of exposure and the virus subtype, as well as the naiveté of the animals. Fulminating disease of the upper respiratory tract, classical infectious bovine rhinotracheitis, is observed following infection with BHV1 subtypes 1 and 2a in unvaccinated animals or herds with no prior history of BHV1 infection (148). Endemic infection is more common in most regions of the world; typically, seropositive rates approach 40% of animals within herds (22). When BHV1 infection is endemic, or in herds where vaccination is practiced, clinical respiratory disease is mild or inapparent and most often observed in young animals (140). It is this form of disease which is associated with predisposition to pneumonic pasteurellosis or other bacterial pneumonias. Infection with BHV1 can occur simultaneously with other respiratory viruses, most commonly with BVDV and PI3.

At least some of the mechanisms by which BHV1 predisposes to bacterial pneumonia have been deduced from study of experimental infection. Intranasal aerosol exposure of neonatal or weanling calves to BHV1 resulted in mucosal lesions of the pharyngeal tonsil, characterized by an initial loss of microvilli and goblet cells which progressed to necrosis of the epithelium and adjacent lymphoid tissue and leukocyte exudation (117). Briggs and Frank (25) observed illness and increased nasal mucus 3 to 10 days after intranasal exposure of calves to BHV1. Various measures of serum leakage and cell death increased on day 3 and peaked 5 to 7 days postinfection, and increased elastase activity preceded colonization by M. haemolytica. These changes may facilitate bacterial colonization by cleavage of epithelial cell surface fibronectin and mucus and exposure of receptors. An earlier study demonstrated that intranasal vaccination with live infectious bovine rhinotracheitis virus vaccine appeared to enhance bacterial colonization of the upper respiratory tract as determined from nasal and tracheal swabs (152). Following endobronchial inoculation of BHV1, infection could be demonstrated in bronchial, bronchiolar, and alveolar epithelial cells and resulted in degeneration and focal necrosis of the epithelium in the lower respiratory tract. Both virus and viral antigen could be demonstrated in desquamated epithelial cells and alveolar macrophages recovered by bronchoalveolar lavage (88). Conlon and coworkers (40) demonstrated impairment of the relaxation response of tracheal and bronchial smooth muscle following aerosol challenge and suggested that disruption of normal homeostatic bronchodilatory mechanisms may predispose infected animals to secondary bacterial infections due to excessive airway constriction and subsequent compromise of lung defenses. The composition of lung surfactant is also affected by infection with BHV1 or PI3, potentially altering its effects on inhaled bacteria (51).

Other innate defenses may be compromised by BHV1 infection. Warren et al. (145) observed reduced influx of neutrophils into the lungs of BHV1-infected calves in response to subsequent challenge with M. haemolytica and speculated that the virus infection altered the cytokine-mediated responsiveness of the lung endothelium. This agreed with an earlier study which demonstrated impaired direct migration, ingestion of bacteria, and nitroblue tetrazolium reduction by neutrophils following experimental (1 to 7 days) or natural (1 to 28 days) infection, while random migration, adherence, and aggregation were increased (45).

Alveolar macrophages are permissive to productive and nonproductive infection with BHV1. Bovine alveolar macrophages harvested 6 days after experimental infection with BHV1 or PI3 had reduced expression of Fc or C3b receptors and were significantly impaired in their ability to phagocytize opsonized bacteria (29). This impairment may be cytokine mediated. In vitro infection of alveolar macrophages with BHV1 had no significant effect on receptor-mediated phagocyte binding, but the addition of lavage fluids from calves infected by aerosol 6 days previously decreased both antibody Fc-mediated and complement C3b-mediated binding (30). In vitro infection of bovine alveolar macrophages with PI3, BVDV, or BHV1 also results in increased procoagulant activity, suggesting that initial viral infection may induce fibrin deposition in alveoli prior to establishment of a secondary bacterial infection (91).

BHV1 infection may affect antigen-specific as well as nonspecific defense mechanisms. Several researchers have demonstrated that the mitogenic response of peripheral blood mononuclear cells stimulated by concanavalin A is suppressed during BHV1 infection. This effect was associated with a deficit of responder T cells, specifically, a selective depletion of circulating CD8 cells coincident with increased T helper (CD4 cell) activity as indicated by elevated levels of interleukin 2 (IL-2) production 2 to 5 days postinfection (58). However, Carter and coworkers (35) found that proliferation in response to IL-2 by IL-2-dependent lymphocyte cultures was reduced, suggesting potential for failure in the induction phase of antigen-specific immunity despite increased T helper activity. In that study, inhibition of mitogenesis approached 100% even though less than 1 cell in 1,000 was productively infected with BHV1. In addition, lymphopenia is observed in vivo 2 to 8 days postinfection with BHV1. There is a significant decrease in the percentage of T cells and non-T, non-B cells but a significant increase in B cells and monocytes. These monocytes and B cells have increased expression of Fc receptor and an apparent decrease in major histocompatibility complex (MHC) class II expression, suggesting a bias against antigen presentation (58).


Bovine PI3 has been associated with both acute and chronic pneumonia in cattle. In one recent study of 120 calves transported to western feedlots in the United States, 104 (87.5%) were treated for UBRD and 16 (13.3%) died. PI3 was isolated from seven of nine lungs cultured, and 71 of 104 surviving calves (68.3%) seroconverted to PI3 (55). Infection with PI3 is often concurrent with BHV1 and/or BVDV infection. Ghram and coworkers (56) observed that calves infected with BHV1 and PI3 developed clinical signs including fever, cough, and nasal and ocular discharges. Animals infected with both viruses appeared more depressed and showed higher rectal temperatures, while those infected with PI3 alone had milder disease.

Infection with PI3 may predispose to bacterial pneumonia as a consequence of effects on phagocyte function (26). PI3 infection of alveolar macrophages both in vivo and in vitro has been associated with decreased ability to kill bacteria, including inhibition of phagosome-lysosome fusion, and enhanced production of the metabolites of arachidonic acid which may be inhibitory to other phagocyte functions (71). Dyer and coworkers (48) demonstrated that infection of bovine alveolar macrophages with PI3 inhibited oxygen-dependent bacterial killing by selective inhibition of calcium-independent phosphatidylserinediglyceride-dependent protein kinase C activity. Such inhibition of the oxygen-dependent bactericidal function of macrophages and disturbances in signal transduction would contribute to bacterial superinfection. Brown and Ananaba (29) found that alveolar macrophages harvested from lavage fluid 6 days after infection with PI3 had reduced expression of Fc or C3b receptors, which significantly impaired their ability to phagocytize opsonized bacteria. Subsequent studies confirmed these findings and showed that the addition of lavage fluids from infected calves decreased both Fc-mediated and C3b-mediated binding in macrophages harvested from uninfected animals, suggesting that a cytokine or other soluble factor mediated this inhibition (30).

PI3-infected macrophages or monocytes have been shown to depress mitogen-induced lymphocyte proliferation in vitro while simultaneously causing nonproductive or abortive infection in lymphocytes (15). While this effect on lymphocytes may reduce viral infectivity in vivo, it also has the potential to inhibit the protective immune response. The same researchers subsequently showed that PI3-infected alveolar macrophages inhibit the lymphocyte response to concanavalin A and IL-2 and speculated that this was due to infection of lymphocytes by cell-to-cell contact with infected macrophages (16). Other workers (141) suggest that PI3 adversely affects lymphocyte proliferation because it interferes with the accessory role of macrophages.

Despite the effects of PI3 on lymphocytes, infected animals do mount antigen-specific immune responses to the virus. Bovine peripheral blood lymphocytes were shown to have maximum cytotoxic activity against PI3-infected cells between 5 and 9 days postinfection (14). This corresponds temporally with the optimum time for bacterial secondary infection in experimental challenge models. Killing of PI3-infected cells in vitro has been observed with neutrophils, alveolar macrophages, and lymphocytes (23). When the target cells are virus-infected phagocytes or lymphocytes, host defenses against other organisms would be compromised. The same workers (23) found that addition of specific antibody increased killing by neutrophils, monocytes, and lymphocytes but inhibited killing by alveolar macrophages. Subsequent in vivo work confirmed that alveolar macrophages were capable of killing PI3-infected cells early in infection, but this capability declined after antibodies to PI3 were detectable, 5 days postinfection (2). Other researchers found that cultured alveolar macrophages release tumor necrosis factor alpha (TNF-α) when stimulated by exposure to PI3 in the presence of neutralizing antibodies (21). It is probable that the inhibitory effects of antiviral antibody on infected macrophages alter the ability of these cells to deal with other organisms.

PI3 infection has the potential to alter airway smooth muscle reactivity. Four days after experimental intratracheal inoculation of PI3 in guinea pigs, Folkerts and coworkers (52) observed a 45% increase in histamine-induced contraction of tracheal smooth muscle, and the number of inflammatory cells in the airways was 1.5 times higher than in controls. This tracheal hyperreactivity was also associated with an increase in inflammatory bronchoalveolar cells. Similarly, 6 days after aerosol infection of calves with PI3, there was increased histamine content in mast cells and enhanced ionophoreinduced release (90). These reactions, typically associated with type 1 hypersensitivity responses, suggest inflammatory responses to PI3 infection which could ultimately have adverse effects on respiratory clearance and which might facilitate pulmonary colonization by bacteria.


BRSV has been established as a common pathogen in respiratory disease (10, 13, 127, 128) and has been demonstrated to interact with bacterial pathogens in establishing pneumonia in cattle (101, 127). BRSV occurs within the cattle population around the world. Although difficult to isolate, the prevalence of the virus is inferred by the presence of BRSV-specific serum antibodies (7, 13). The most likely method of transmission of BRSV from animal to animal is by aerosol and through contaminated nasal secretions. Three to 5 days after infection, clinical disease occurs (20). Spread of the virus is rapid within a naive herd, and high morbidity rates (60 to 80%) have been reported by various researchers, including van der Poel et al. (139). Severe clinical disease has been related to age and is most commonly seen in calves less than 6 months old (99).

BRSV has been demonstrated to infect both ciliated and nonciliated epithelial cells in the respiratory tract, causing necrotizing bronchiolitis and interstitial pneumonia (31, 32, 36, 49). Infiltration of the lung by neutrophils and other inflammatory cells is presumed to be due to cytokine and chemokine release from virally infected cells (32).

Both Trigo et al. (138) and later Sharma and Woldehiwet (118) demonstrated that lambs which were experimentally infected with BRSV were more susceptible to infection with M. haemolytica than those not exposed to the virus. Although not conclusively proven, it is thought that BRSV alters the normal function of macrophages, neutrophils, and lymphocytes. In vitro challenge of peripheral blood mononuclear cells with BRSV decreases the proliferative response to phytohemagglutinin (86, 119).

Another closely related pneumovirus, human respiratory syncytial virus (HRSV), has been shown to infect immune cells, resulting in immunosuppression in the host (46). Recent studies with HRSV have demonstrated high-level expression of chemokines by virus-infected epithelial cells of the lower airway (156), suggesting a mechanism for recruitment of neutrophils, monocytes, eosinophils, NK cells, T lymphocytes, and dendritic cells into airways. Although necessary for defense against the infection, immunopathology associated with this inflammatory response no doubt contributes to respiratory pathology. Additionally, HRSV has been reported to stimulate production of inflammatory mediators, including gamma interferon (IFN-γ) and prostaglandins (98, 105). Keles and coworkers (66) demonstrated that both inactivated BRSV and live BRSV were capable of suppressing the lymphocyte proliferative response to phytohemagglutinin, probably through release of inhibitory substances from mononuclear cells. Other researchers were able to demonstrate that mononuclear cells exposed to HRSV released inhibitors to IL-1 (86, 111, 114) and IFN-α (105), resulting in decreased cellular function. Furthermore, alveolar macrophages which have been infected with BRSV produce a decreased level of nitric oxide (116), an important bacteriocidal compound produced in response to bacterial invasion. Still, others argue that the level of replication of BRSV in alveolar macrophages is low and the impact on alveolar macrophage function is questionable (12). There is some indication that not all strains of BRSV produce the same effect on pulmonary immune cell function (137).


The role of BVDV in shipping fever pneumonia in feedlot cattle remains controversial in spite of decades of research (59, 100, 106). BVDV has been reported to be the virus most commonly isolated from pneumonic lungs of cattle (107). Serological evidence suggests that multiple infections with respiratory viruses are common in young calves suffering from respiratory disease and that BVDV is present in the majority of these multiple infections (55, 110). In experimental studies, inoculation of susceptible calves with BVDV alone typically leads to mild or moderately severe respiratory disease (19, 27, 104), but labored abdominal breathing with fevers over 41°C has been noted with a Canadian type 2 noncytopathic strain (9). In some studies, infection with BVDV followed by inoculation, after several days, with M. haemolytica has resulted in severe pneumonic disease (102, 104). In short-term studies, Lopez and coworkers did not find an effect of BVDV infection on lung clearance of M. haemolytica; the authors, however, did not reject the possibility that other mechanisms besides impaired bacterial clearance could mediate pathogenic effects of BVDV (80, 81). Differences in pneumopathogenicity of BVDV strains have been documented (65, 102); both cytopathic and noncytopathic strains were represented among those classified as pneumopathogenic.

In epidemiological studies, rates of seroconversion to BVDV vary widely (59), as do the risks of developing pneumonia associated with this seroconversion. A number of feedlot studies, however, have found serological support for a role of BVDV in UBRD (82, 83, 89). Several studies have examined the clinical effects of concurrent infection with BRSV and BVDV (27, 50). Clinical signs of respiratory disease were more severe with mixed infection, and immune responses to BRSV were considered to be delayed by the presence of BVDV infection. Potgieter and coworkers investigated the effects of experimentally induced BVDV infection on respiratory infection with BHV1 (103). Inoculation of calves with BHV1 alone was associated with isolation of virus mainly from the upper respiratory tract, with lower titers of virus present in lung tissue. Inoculation with BVDV 7 days prior resulted in high titers of BHV1 being isolated from both upper and lower respiratory tracts and from liver, spleen, brain, and intestinal tract tissues, indicating impairment of host defenses. BVDV has also been reported to influence clearance of endogenous bacteria in the lungs, leading to bacteremia in BVDV-infected calves (109).

In vivo and in vitro studies have documented multiple effects of BVDV on the functional capabilities of the bovine immune system. Welsh and coworkers (147) have investigated effects on alveolar macrophages. Macrophages recovered from bronchoalveolar lavage fluids from calves experimentally infected with cytopathic BVDV had decreased expression of both Fc and complement receptors. Phagocytic and microbicidal activities were impaired, as well as the ability to exert a chemotactic effect on neutrophils. Effects on receptor expression and phagocytic ability could also be shown in alveolar macrophages from uninfected calves infected in vitro (79, 147). It is anticipated that these effects on alveolar macrophages would reduce the ability to clear M. haemolytica and other bacterial pathogens from the lung.

Olchowy and coworkers have investigated the effects of cytopathic and noncytopathic BVDV strains on the procoagulant activities of alveolar macrophages (91). Inoculation of cell cultures with BVDV increased procoagulant activity. At low doses of virus, the presence of lipopolysaccharide (LPS) stimulated a further increase. These findings suggest that in the bovine lung, infection with BVDV can lead to fibrin deposition in the alveoli, impeding clearance of bacteria and promoting colonization.

BVDV has been shown to increase production of prostaglandin E2 by monocytes in vitro (146) and is associated with decreased expression of MHC class II molecules on peripheral blood mononuclear cells in infected calves (9), effects anticipated to reduce or delay antigen-specific immune responses.

Bovine Adenovirus

Although adenovirus infections of cattle were documented before 1960 (68), their role in clinical diseases in cattle remains controversial. Ten serotypes of bovine adenovirus have been identified (155). The virus is encountered worldwide in cattle, with particular serotypes predominating from time to time in a particular geographic region (33). Although adenoviruses have been isolated from the respiratory tracts of pneumonic calves, isolation from clinically healthy cattle is more frequent (136). Some serologic studies have supported a role for bovine adenoviruses (11, 34, 76) in bovine respiratory disease, while evidence was lacking in other studies (13, 128). Several serotypes of bovine adenovirus have been shown to induce disease in newborn colostrum-deprived calves (33, 75). In several studies, vaccination reduced the incidence of pneumonic disease in calves (33, 85).

Adenovirus infection is common in sheep, in which, in contrast to the situation in cattle, isolation of adenovirus from diseased animals is more common than from healthy animals (28). Six serotypes of ovine adenoviruses are recognized (155). Infection of colostrum-deprived lambs with serotype 6 ovine adenovirus leads to clinical respiratory disease, and infection with both adenovirus and M. haemolytica leads to more severe and more prolonged disease (42, 74).

Adair and coworkers have examined the effects of bovine adenovirus type 1 on bovine alveolar macrophages in vitro (3). A decrease in expression of Fc and complement receptors and a decrease in the ability to phagocytose and kill Candida krusei were noted. Effects of a type 2 strain of adenovirus were less dramatic. The effects of human adenovirus infection on adhesion of Haemophilus influenzae and Streptococcus pneumoniae to respiratory epithelial cells in vitro was investigated by Hakansson and coworkers (60). When serotypes of adenovirus associated with respiratory tract infections were used, binding by adherent strains of S. pneumoniae was increased. The authors suggested that expression of receptors used by S. pneumoniae was increased by adenovirus infection.


Interest in BCV as a respiratory pathogen contributing to BRD (pneumonic pasteurellosis) in feedlot calves is relatively recent. Work by Storz and coworkers (125) in the mid-1990s documented high rates of isolation of BCV from nasal swabs collected on arrival at feedlots from calves with respiratory disease. More recent studies have confirmed this observation (78, 124) and noted, in addition, that high titers of serum immunoglobulin G2 (IgG2) antibody to BCV were associated with protection against respiratory disease. A prospective study that included monitoring of nasal shedding of M. haemolytica, as well as BCV and five other respiratory viruses, also found that calves that remained clinically normal had high titers of serum antibody to BCV on feedlot arrival and did not subsequently shed BCV (123). BCV was isolated from lung tissue of 18 calves and M. haemolytica was isolated from lung tissue of 25 calves of a total of 26 calves dying with respiratory disease. Nasal shedding of BCV and serological evidence of viral infection in 12 lots of feedlot cattle in Ohio, Texas, and Nebraska were examined by Lathrop and coworkers (72, 73). Shedding of BCV varied from 0 to 36%, depending on the origin of the calves, year of study, and location of the feedlot. Over 60% of the calves seroconverted to BCV by 28 days after feedlot arrival. Calves shedding BCV and responding serologically had an estimated 1.6-times-increased risk of being treated for respiratory disease. Canadian studies examining calves in seven feedlots in Alberta and Ontario found that over 80% of calves have serum antibodies to BCV on feed-lot arrival (84, 89). Rates of seroconversion to BCV in the first month in the feedlot varied from 50 to 100% in different groups. The very high incidence of BCV exposure in these studies made inferences about the causal role of BCV in respiratory disease difficult.

Laboratory studies have suggested several mechanisms whereby respiratory infection with BCV may decrease resistance to bacterial pathogens. Respiratory isolates of BCV with acetylesterase activity capable of releasing acetate from the normal glycocalyx lining of the bovine respiratory tract have been found. It is postulated that this modification of the glycocalyx enhances adhesion of M. haemolytica and P. multocida to host cells in the lower respiratory tract (77, 123, 126).

Oleszak and coworkers have investigated binding of the Fc portion of immunoglobulins by S peplomer proteins of various coronaviruses (9296). The S proteins of mouse hepatitis virus, transmissible gastroenteritis virus, and BCV bind immunoglobulins of murine, swine, and bovine origins, respectively, but do not bind F(ab′)2 fragments. This property could interfere with opsonization of both bacteria and viruses by preventing interaction of antibodies with Fc receptors on macrophages and neutrophils or by interfering with binding of complement component C1q with the Fc portion of bound antibodies, preventing initiation of the classical pathway of complement activation. Either scenario would decrease uptake and destruction of pathogens and permit their replication.

The M and E structural proteins of coronaviruses (including transmissible gastroenteritis virus and BCV) have been shown to be potent inducers of IFN-α synthesis by peripheral blood mononuclear cells (17, 18, 37). IFN-α is an early cytokine and has proinflammatory properties in common with TNF-α and IL-1. IFN-α has synergistic effects with TNF-α and IL-1, and each can induce expression of the other (142). TNF-α and IL-1 both induce infiltration of neutrophils into the lung and thus are of central importance in the pathogenesis of bacterial pneumonias. High-level expression of IFN-α theoretically could contribute to either protection or disease pathogenesis; work with porcine respiratory coronavirus in pigs suggests, however, that infection with respiratory coronavirus in combination with exposure to bacterial LPS leads to enhanced expression of both TNF-α and IL-1 and exacerbation of respiratory disease (143). Experimental evidence suggests that IFN-α induces expression of adhesion molecules by endothelial cells (142) and mediates infiltration of CD8 T lymphocytes into lung tissue (57, 58). The implications of these observations for polymicrobial infections involving BCV in cattle have not been explored experimentally.

Bacterial Pneumonia in Cattle


The severe pneumonic damage characterized by pulmonary invasion of M. haemolytica and other bacteria is associated with the production of virulence factors which facilitate colonization of the lower respiratory tract (39). Production of neuraminidase and neutral protease may enhance the bacterium's ability to adhere and colonize the respiratory epithelium (151). Lung injury characterized by vascular damage, excess fibrin effusion, and neutrophil infiltration results from the host's response to LPS produced by this gram-negative organism (1, 150, 151). The large influx of neutrophils into the lung is a hallmark of infection with M. haemolytica and has been associated with pathology, possibly as a result of neutrophil lysis by the leukotoxin (Lkt) of M. haemolytica (133, 154). Animals chemically depleted of neutrophils and then challenged with M. haemolytica were demonstrated to have reduced lesions (24).

The Lkt of M. haemolytica, a member of the RTX family of toxins, is a pore-forming, Ca2+- dependent cytolysin with specificity for ruminant leukocytes and platelets (38, 120). Low concentrations of Lkt activate neutrophils and induce apoptosis of leukocytes (43, 122). This may be important in the progression of pneumonic pasteurellosis, since apoptosis would limit the initial inflammatory response, allowing the organism to colonize and replicate within the lung (131). Additionally, Lkt has been shown to suppress leukocyte respiratory burst, stimulate lysosomal degranulation, and inhibit phagocytosis and bacterial killing (44, 151). Any of these activities would enhance the organism's ability to establish within the lung.

Other pathogens often associated with bacterial pneumonia in cattle include P. multocida and H. somnus (87). Like M. haemolytica, both are normal inhabitants of the upper respiratory tract of cattle. P. multocida is considered to be less virulent than M. haemolytica, and in experimental challenge studies, more organisms are required to produce primary pneumonia (8). The organism may cause acute fibrinous bronchopneumonia or may be associated with chronic suppurative bronchopneumonia. Very little is known about the virulence factors of P. multocida that contribute to pulmonary pathogenicity. The capsular polysaccharide may allow the organism to evade phagocytosis and complement-mediated killing (44). Production of neuraminidase has been correlated with growth of P. multocida in vitro (149). Although not serologically related to the neuraminidase of M. haemolytica, this neuraminidase may also enhance colonization and adhesion in deeper pulmonary structures (87).

In general, pneumonia attributed to H. somnus is more subacute or chronic than that caused by infection with either M. haemolytica or P. multocida (101, 121). Lesions associated with H. somnus infection include necrotizing bronchiolitis and alveolitis. It is unclear if necrotizing airway lesions are due to colonization by this organism or a predisposing infection with respiratory viruses such as BRSV (32). One of the important virulence factors of H. somnus is thought to be its lipooligosaccharide (LOS), which functions similarly to the LPS of M. haemolytica and P. multocida (41). LOS of H. somnus is responsible for endothelial changes that can trigger thrombosis in alveolar vessels and cause subsequent lung damage (132). Additionally, H. somnus can trigger apoptosis of bovine neutrophils (153), probably a mechanism by which the organism evades killing by the host.

Mycoplasma and Ureaplasma Species

Mycoplasma mycoides subsp. mycoides (small colony type [SC]) (144), M. bovis, M. dispar, and U. diversum have been associated with respiratory tract disease in cattle (61, 112). M. mycoides subsp. mycoides SC causes contagious bovine pleuropneumonia, an enzootic disease in cattle in Africa, Asia, and parts of Europe with major economic impact (115). M. bovis, M. dispar, and U. diversum contribute to respiratory disease in housed calves and feedlot cattle. M. bovirhinis has been isolated from the lower respiratory tract of calves (4, 97), but evidence of a role in lung disease remains elusive. Epidemiological evidence points to a role of M. bovis and M. dispar in pneumonia of feedlot calves (83, 113). Isolation of multiple species of mycoplasmas from pneumonic lungs has been noted in some studies (69, 70, 134).

M. dispar has effects on tracheal epithelial cells that range from ciliostasis (63) to degenerative changes and death (5). Experimental infection of calves with M. dispar leads to decreased clearance of Serratia marcescens (5), suggesting that M. dispar infection facilitates infection by other bacterial species. M. bovis infection, in contrast, has less effect on the function of ciliated epithelium but invades deeper into lung parenchyma, incites a stronger cellular response, and induces more lung damage (63).

Mycoplasma species can alter phagocytic function. In the absence of opsonizing antibodies, capsular material of M. dispar not only inhibits uptake of itself, but also prevents activation of macrophages by other stimuli (6). In vitro, killing of Escherichia coli by bovine neutrophils is inhibited by mycoplasma products (62). M. bovis interacts with bovine neutrophils in vitro to impair the respiratory burst (135).

Some mycoplasma species exhibit mitogenic activity for B and T lymphocytes, and a peptide of Mycoplasma arthritidis has been shown to be a superantigen for T cells. Mitogenic stimulation of B and T cells induces proliferation of lymphocyte clones which are irrelevant for protection (against mycoplasmas and coinfecting organisms) but may contribute to autoimmune disease (112).

U. diversum has been shown to have protease activity against bovine IgA (67). Because this protease activity cleaves IgA regardless of the antibody specificity, it affects immunity to other pathogens at the same mucosal site and may augment other infectious processes.


In conclusion, there is ample evidence to support the synergistic effect of combined viral and bacterial infections in bovine respiratory disease. The fact that predisposition can be attributed to more than one virus and the realization that no single bacterium is responsible for the resulting pneumonia support the notion that despite differences in the details of mechanisms that facilitate secondary infection, the overarching effect is impairment of host defense. This effect may be mediated by direct action of the organism, for example, destruction of the epithelial barrier through infection of epithelial cells, but indirect effects which alter the innate and/or specific immune response are key in these scenarios. Such effects include alterations in mucus secretion or the activity of cilia which affect the mucociliary escalator; impaired phagocytic uptake and/or killing by alveolar macrophages, a dysfunction which impedes clearance of inhaled organisms from the deeper reaches of the lung; alterations in neutrophil migration and activity which impair augmentation of clearance through inflammatory recruitment; inhibition of the responsiveness of lymphocytes to mitogens and antigens which limits antigen-specific responses to the organisms; and the apparently paradoxical effects of specific antibodies which can accentuate the defects of virus-infected phagocytes and which may lead to further loss of defense though complement-mediated killing of infected neutrophils, macrophages, monocytes, lymphocytes, or epithelial cells. Understanding the reactions which facilitate and result from mixed infections is critical for the development of effective measures for control and prevention of bovine respiratory disease.


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