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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 11Cooperation between Viral and Bacterial Pathogens in Causing Human Respiratory Disease

and .

Author Information

1 and 2.

1 Medical School, University of Birmingham, Birmingham, B15 2TT, United Kingdom.
2 School of Biosciences, University of Birmingham, Birmingham, B15 2TT, United Kingdom.

Viruses that most commonly attack the human respiratory tract are influenza virus, parainfluenza viruses, respiratory syncytial virus (RSV), adenoviruses, measles virus, rhinoviruses, and coronaviruses (64). The main bacterial pathogens found in this tract are Streptococcus pneumoniae, Streptococcus pyogenes, Haemophilus influenzae, Staphylococcus aureus, Neisseria meningitidis, Mycobacterium tuberculosis, Bordetella pertussis, and, in immunocompromised patients, Pseudomonas aeruginosa (37). This chapter describes how some of these viruses and bacteria can cooperate to cause respiratory diseases which are more severe than those caused by either pathogen alone. Clinical, pathological, and epidemiological observations on natural disease, which suggest that such cooperation occurs, are examined first. This is followed by experiments using either animal models or, occasionally, human infections which prove the case. Finally, possible mechanisms to explain the increased severity of disease arising from dual infections are explained.

Observations on Natural Disease

The best and most studied example of virus-bacterium cooperation in the respiratory tract involves influenza virus. Influenza in humans is predominantly an upper respiratory tract infection; it is not usually fatal, but sometimes the lungs become infected, and this may have lethal consequences (51, 64). Most deaths in influenza epidemics arise from secondary bacterial infections, which were a scourge to humankind before the advent of antibiotics and even now are troublesome (6, 15, 27, 51, 60, 90). The bacteria concerned are predominantly S. pneumoniae, H. influenzae, S. aureus, and N. meningitidis (6, 15, 27, 51, 60, 90, 100). Indeed, the incidences of influenza, pneumococcal infection, and meningococcal disease show a seasonal association: they all peak in the winter months (14, 52). During the 1918 to 1919 influenza pandemic, around 40 million people died. Some deaths appeared to be due to viral pneumonia, since they occurred rapidly after the onset of symptoms, often with acute pulmonary hemorrhage or edema. However, clinical and pathological evidence indicates that the majority of people succumbed to secondary bacterial pneumonia (100).

In respiratory disease of children, cooperation of bacteria with RSV may occur more frequently than with influenza virus. For example, in a serological study of the etiology of community-acquired pneumonia in children, 39% of the children with viral infection had a concomitant bacterial infection, and the most frequent combination for those under the age of 5 years was RSV with S. pneumoniae (38). As with influenza, both RSV infection and pneumococcal disease peak in the winter months (52). RSV has been associated with other bacteria too, e.g., B. pertussis (2, 68) and S. aureus (12). Other respiratory viruses have been implicated in bacterial interactions but to a lesser degree. Human parainfluenza virus was found, together with S. pneumoniae, in an outbreak of pneumonia in a long-term care facility (26). Adenoviruses also may predispose patients to respiratory bacterial infections (21, 30), and associations between adenovirus and B. pertussis in severe respiratory disease of children have been noted (2, 93). Measles virus seems to exacerbate tuberculosis (24). Also, in 182 cases of measles-associated pneumonia of children, mixed infection was found in 53% of the patients, with S. pneumoniae being the most common finding in blood cultures (74). In contrast to most respiratory viruses, rhinoviruses and coronaviruses that cause the common cold appear to act alone. In 200 young adults with common colds, virus etiology was established for 138 cases (105 had rhinoviruses, and 17 had coronaviruses), but evidence of bacterial infection was found in only 7 of the patients (65).

In sudden infant death syndrome (SIDS), a common cause of postperinatal mortality (31, 69), there is often a history of upper respiratory tract infection and inflammatory changes are sometimes visible at postmortem (13, 104). Several respiratory viruses have been associated with SIDS; they include RSV, influenza virus, parainfluenza virus, adenovirus, and rhinovirus (91, 110). Also, changes in bacterial populations in the nasopharynx, particularly an increase in S. aureus and enterobacteria, have been associated with SIDS (9, 101).

These observations on naturally occurring human disease clearly show that viruses and bacteria are found together in severe respiratory disease. However, there is no specific evidence for cooperation between them except for in influenza, for which histopathology indicates that most deaths following viral infection are due to secondary bacterial infections.

Proof That Viruses Cooperate with Bacteria in Producing Disease

In many experiments using animal models, bacterial infections have been superimposed at various times after inoculation of viruses. Enhancement of bacterial infection was demonstrated by comparisons of the bacterial contents of appropriate tissues with those of animals receiving bacteria alone. Exacerbation of disease was shown by more-severe lesions or higher death rates than for animals receiving either the bacteria or viruses alone. The classical investigation using an animal model was that of Shope in 1931 (94) using influenza virus and H. influenzae in pigs. However, mice have been the experimental animals used for most investigations. Examples are as follows. Influenza virus enhanced respiratory infections with pneumococci (36, 59, 97), staphylococci (43), Listeria monocytogenes (28), group B streptococci (49), and Bacillus thuringiensis (39). Sendai virus enhanced respiratory infections with Mycoplasma pulmonis (41). Reovirus enhanced staphylococcal infection (53), and cytomegalovirus enhanced P. aeruginosa infection (33). Observations for other animal models included increased infection with H. influenzae in RSV-infected cotton rats (71), the effect of influenza virus on colonization of the nasopharynx of chinchillas by different phenotypes of S. pneumoniae (102), and enhanced streptococcal infection following influenza virus infection of ferrets (10, 29). Neonatal ferrets infected with influenza virus provided an animal model for SIDS. An intranasally administered virulent strain (clone 7a) killed the neonates, and the pathology of some was akin to that seen in SIDS. In contrast to the virulent strain, killing of the neonates by a less virulent strain (PR8) could be prevented by antibiotic treatment, indicating that it was due to virus exacerbation of naturally acquired bacterial infection (42).

For obvious reasons, humans have not been deliberately infected with respiratory viruses followed by bacterial pathogens to study the progress of subsequent bacterial infection as described above for animal models. However, the effect of experimental influenza A virus infection of volunteers on selection of pathogens from the natural nasopharyngeal flora has been studied; S. pneumoniae was not isolated from any subject prior to virus challenge but was isolated in substantial numbers from 15% of the subjects on the sixth day following challenge (105). Also, cells and fluids have been harvested, either from patients with natural infections or volunteers experimentally infected with viruses, and interacted with pathogenic bacteria in vitro in biological tests related to infection. For example, S. aureus, H. influenzae, and S. pneumoniae showed enhanced adherence to pharyngeal cells obtained from volunteers infected with influenza virus compared with cells from uninfected controls (23). Other examples are given below.

Mechanisms of Cooperation

To cause disease, microorganisms must infect mucous surfaces, penetrate into the tissues, grow in the tissue environment, inhibit host defense mechanisms, and cause damage to the host (96). Viruses can increase the ability of bacterial pathogens to achieve one or more of these steps. Also, there is one example of bacteria enhancing viral growth in host cells. The mechanisms are discussed in relation to infections of the respiratory tract.

Infection of the Mucous Surface

Bacterial infection of respiratory tract surfaces could occur more easily if mucociliary clearance was impaired by virus attack. In fact, bacterial pulmonary infection is common in primary ciliary dyskinesia (80). Viruses are thought to impair ciliary action. RSV infection caused a loss of cilia from human bronchial cells in vitro (103). Influenza virus infection caused damage to ciliated columnar epithelium and the bronchial epithelial lining (107). Nevertheless, the results of early work with animal models indicated that virus infection does not impair mucociliary clearance. In mice infected with influenza virus, ciliated epithelium was damaged but mucociliary clearance was unaffected (34). Similarly, in mice infected with Sendai virus, tracheobronchial clearance of inhaled radiotracer-labeled bacteria was not significantly altered (30).

Enhanced adherence to host cells by bacteria would also increase infection of the respiratory tract, and this does occur as a result of virus attack. This is proved by two types of experiments: adherence to cell lines infected with virus in vitro (Table 1) and adherence to cells of virus-infected animals or people examined either in vivo or in vitro (Table 2). Now there is much interest in the molecular bases for the enhanced adherence.

Table 1. Enhanced bacterial adherence to cell lines when infected with viruses in vitro.

Table 1

Enhanced bacterial adherence to cell lines when infected with viruses in vitro.

Table 2. Enhanced bacterial adherence to tissues or cells of virus-infected animals or humans.

Table 2

Enhanced bacterial adherence to tissues or cells of virus-infected animals or humans.

Virus-induced change in host cell membranes is the most likely cause of increased bacterial adherence. For example, viral glycoproteins expressed on host cell membranes could act as receptors for bacteria. In the case of influenza virus, both its hemagglutinin (HA) and neuraminidase are inserted into host cell membranes (64). An early study (88) indicated that influenza virus HA on infected MDCK cells was a receptor for group B streptococci because the adherence was blocked by antibodies to the HA. Also, the adherence could be blocked by treatment with neuraminidase (17), which suggests that adherence was mediated through sialic acid on the HA oligosaccharide. In a more recent study, alteration in the glycoconjugate structure of murine nasopharyngeal mucosae brought about by influenza virus infection was detected by changes in lectin binding patterns (40).

Neither antibody nor neuraminidase treatment inhibited increased staphylococcal adherence to influenza virus-infected MDCK cells, so other receptor mechanisms must also be involved. Two studies suggest that these mechanisms are complex. The bacterial adhesins mediating the binding of staphylococci to virus-infected cells are more heat labile than those involved in staphylococcal binding to uninfected cells, and two staphylococcal proteins, clumping factor and protein A, act as adhesins for normal but not virus-infected cells (18, 87). The natures of the cell receptors are unknown. One possible mechanism for staphylococcal adherence to virus-infected cells in vivo was suggested by an earlier study (3). Protein A on the surface of staphylococci is known to interact with antibody (37). In vivo, infected cells may be coated with viral antibody, thus providing a receptor for staphylococcal protein A. Indeed, adherence of protein A-containing staphylococci, but not that of strains lacking protein A, was enhanced by treating influenza virus-infected cells with antibody (3). This mechanism could operate for other viruses.

Glycoproteins F and G of RSV are inserted into the membrane of infected HEp-2 cells, and glycoprotein G is involved in the increased binding of N. meningitidis to these cells (77). Also in HEp-2 cells, RSV infection up-regulated normal host cell receptors such as CD14, CD15, and CD18, and CD14 and CD15 were associated with the increased adherence of a nonpiliated strain of N. meningitidis (78).

Extracellular matrices can provide a vehicle for cross-linking bacteria with virus-induced alterations of host cell membranes. For example, the adhesion of group A streptococci to influenza A virus-infected cells is enhanced by addition of fibrinogen (86). Oligosaccharides on neuraminidase, HA, or both, expressed on virus-infected cell surfaces, may be responsible for binding the fibrinogen because addition of tunicamycin, an inhibitor of glycosylation of viral proteins, decreased the fibrinogen-mediated adherence (86).

Penetration into the Tissues

The denudation of epithelial cells that results from infection with influenza virus must aid penetration into the tissues. Thus, staphylococci appear to attack only those parts of the respiratory tract damaged by viral attack (67). Epithelial damage by other viruses could have similar effects.

Growth in the Tissue Environment

An early study indicated that fluid exuded onto mucous surfaces as the result of virus attack could increase bacterial growth. In mice, infection with influenza virus alone induced lung edema, and virus-free edema fluid from such mice enhanced the ability of pneumococci to produce pneumonia in other mice not previously infected with influenza virus (35). The factors involved are unknown.

Inhibition of Host Defense Mechanisms

There are three types of defense against bacterial attack that could be inhibited by virus infection: nonspecific humoral factors, such as complement-mediated killing by normal serum; nonspecific phagocytosis by neutrophils and macrophages at the beginning of infection; and the later specific-antibody- and cell-mediated response (96). With regard to humoral factors, some viruses, notably, herpesviruses, poxviruses, and human immunodeficiency virus type 1, are able to interfere with complement, either by incorporation of cellular complement regulatory protein CD55 into the virion envelope or cell membrane (95) or by expression of viral molecules that mimic functions of complement regulatory protein (7). Also, the viruses can bind to the third component of complement, C3, directly or block C5 and properdin binding to C3 (62). However, we are not aware of reports showing that respiratory viruses are able to interfere with the complement system or that these viruses interfere with the action of host humoral factors on bacteria. Viral immunosuppression is dealt with in chapter 19; hence, interference with the nonspecific action of phagocytes is the subject of this section.

Numerous experiments with respiratory viruses show that the capacity of neutrophils and macrophages to deal with bacterial infection is substantially reduced by virus attack. Only a few examples are cited here. Human neutrophils, after interaction with influenza virus in vitro, showed decreased chemotaxis and phagocytic activity in interactions with staphylococci (58). In vivo, rat neutrophil exudation and mobility were depressed by influenza virus infection (82). Macrophage chemotaxis towards bacteria was inhibited by influenza virus infection in vitro (55, 72). Also, experiments with a monocytic cell line (THP-1) showed that RSV depressed tumor necrosis factor alpha production and bactericidal activity against H. influenzae and S. pneumoniae (76). In vivo, influenza virus infection of mice inhibited accumulation of macrophages at inflammatory sites (54) and impaired their capacity to remove staphylococci from the lungs (43). Both ingestion and killing of bacteria by alveolar macrophages are inhibited (109). Inhaled staphylococci were ingested equally by alveolar macrophages of normal mice and those infected with Sendai virus, but the bacteria were killed in the former cells and grew in the latter (30).

With regard to the mechanism of reduction in bactericidal power of neutrophils and macrophages, influenza virus infection impairs lysozyme production by both types of phagocytes (70, 108), while Sendai virus inhibits phagolysosome fusion in mouse alveolar macrophages (44). Superoxide generation is also inhibited in influenza virus-infected phagocytes (19). Interestingly, dual infection of neutrophils with influenza A virus and S. pneumoniae caused significantly more H2O2 production than either pathogen alone, but the increased respiratory burst contributed to diminished neutrophil survival (22). Finally, neutrophil and macrophage apoptosis is accelerated by influenza virus infection (16, 25, 61), and this would decrease the overall antibacterial activity.

Cause Damage to the Host

Bacteria can damage the host by producing toxins and/or inducing cytokines and inflammation (96). There is research regarding SIDS which indicates that viral infection can exacerbate the effect of toxins and the induction of inflammatory cytokines in the respiratory tract.

We noted above that in SIDS there is an increase of S. aureus and enterobacteria in the nasal flora, and it has been suggested that bacterial toxins may contribute to SIDS (66). Staphylococcal enterotoxins and the toxic shock syndrome toxin have been identified in the tissues from over half of SIDS cases from five countries (8). The possibility that virus infection can enhance the lethal effects of bacterial toxins was examined by using the neonatal ferret model for SIDS (45). Staphylococcal α and γ toxins, endotoxin, and diphtheria toxins were lethal for 5-day-old ferrets. Their toxicities were enhanced in 1-day-old animals infected with influenza virus PR8, from 3-fold with staphylococcal γ toxin to 14-fold for staphylococcal α toxin, 84-fold for endotoxin, and 219-fold for diphtheria toxin. No increased viral replication occurred in any tissue; thus, the effects of the toxins were exacerbated by the infection, not vice versa. Neonates died suddenly without clinical symptoms, similarly to human babies dying from SIDS. Pathological examination showed inflammation in the upper respiratory tract, lung edema and collapse, and early bronchopneumonia in the animals treated with toxin and influenza virus but not in those treated with toxin or virus alone. Thus, bacterial toxins could play a role in SIDS, this being more likely with a concomitant influenza virus infection.

The increased toxicity of staphylococcal α toxin and diphtheria toxin may follow from the enhancement of membrane leakage in virus-infected cells. This was detected by the release of α-amino[14C]isobutyric acid from ferret Mpf cells (46). The release, induced by staphylococcal α toxin and diphtheria toxin, was enhanced significantly when the cells had been previously infected with influenza virus PR8, although infection with virus alone did not increase the release of radiolabel compared with that of untreated cells. The mechanism of enhancement of release is unclear, but it occurs 0.5 to 2 h after inoculation and viral membrane-endosome fusion is essential. As stated above, the increase in lethality in the ferret neonatal model is accompanied by inflammation in the upper respiratory tract and lung edema. The reason for these effects may be that the enhanced cellular permeability leads to the release of histamine and other inflammatory mediators such as interleukin 1, tumor necrosis factor, and platelet-activating factor.

Endotoxin has no effect on the membrane permeability of ferret Mpf cells either alone or after influenza virus PR8 infection (46), so changes in membrane permeability probably play no part in the viral enhancement of its toxicity for neonates. However, cytokine release from human peripheral blood leukocytes was increased by infection with influenza virus (63). This release could be the reason for the upper respiratory tract inflammation seen in SIDS and in the neonatal ferret model.

Cleavage of Influenza A Virus HA by Bacterial Proteases

Cell entry of influenza A virus by receptormediated endocytosis requires cleavage of its HA (81). During viral entry, the HA undergoes a conformational change in the acidic environment of the endosome (11). Proteolytic cleavage of precursor HA into HA1 and HA2 exposes the amino-terminal fusion peptide of HA2, resulting in fusion of the viral envelope within the endosomal membrane. Cleavage of HA is important in viral pathogenicity and tissue tropism because it is necessary for spread of infection throughout the host (81). The HAs of mammalian and nonpathogenic avian influenza virus strains are usually cleaved by the proteases in only a few cell types, thus causing only local respiratory infection. On the other hand, the HAs of some avian influenza strains of the H5 and H7 subtypes are cleaved by proteases in a broad range of cells and consequently cause systemic infection. The major structural property that determines the difference in protease sensitivity is the link between HA1 and HA2 in the uncleaved precursor. In HA showing restricted cleavage, the link usually consists of a single arginine residue, whereas highly cleavable HAs have multiple basic residues in this position, forming the consensus sequence R-X-K/R-R (56, 81).

Early studies showed that trypsin was required for cleavage of HA in vitro (57). The HAs of the pathogenic avian viruses are susceptible to host intracellular proteases such as furin; this is not so for the HAs of the mammalian viruses, which are cleaved predominantly by extracellular serine proteases (50, 81, 106). The specific proteases that confer cleavage activation of HA in respiratory infection of humans are not clear, although proteases have been found in nasal washings of children with upper respiratory tract infections (5). Host proteases such as thrombin and plasmin cleave the HAs of some but not all influenza viruses (89).

The proteases of respiratory tract bacteria could contribute to cleavage of influenza virus HA in vivo. This was first shown for the protease of S. aureus (98, 99) and then for those of other bacteria in the respiratory tract, e.g., Streptomyces griseus and Aerococcus viridans (57, 89). HA cleavage by S. aureus and A. viridans not only conferred virus infectivity and the ability to replicate in vitro but also augmented virus replication and pathogenicity in mice (89, 98, 99). Another possible method for bacteria to enhance influenza virus infection is by activation of host proteases which could cause cleavage of HA, e.g., staphylokinase, streptokinase, and a protease from Serratia marcescens which facilitates HA cleavage activation by generating plasmin from plasminogen (1, 89).

Summary and Conclusion

Clinical observations and epidemiology indicate that viruses and bacteria can cooperate to produce more severe respiratory disease in humans than occurs with either infection alone. Experimental studies of mixed infection in animal models and occasionally humans have confirmed this. The mechanisms involved have been probed, and it has been demonstrated that viruses can aid bacteria in all aspects of their pathogenesis, namely, infection and penetration of mucous surfaces, growth in the host environment, interference with host defense, and the causation of damage to the host. Conversely, bacterial proteases may help influenza virus to infect cells of the respiratory tract by cleaving the viral HA.

The important practical conclusion is that successful vaccination against respiratory virus diseases may contribute to protection against bacterial attack.

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