Download Viral–bacterial interactions in the respiratory tract

Journal of General Virology (2016), 97, 3089–3102
Review
DOI 10.1099/jgv.0.000627
Viral–bacterial interactions in the respiratory tract
Carla Bellinghausen,1,2 Gernot G. U. Rohde,1 Paul H. M. Savelkoul,2,3
Emiel F. M. Wouters1 and Frank R. M. Stassen2
Correspondence
1
Department of Respiratory Medicine, NUTRIM – School of Nutrition and Translational Research
in Metabolism, Maastricht University Medical Center+, Maastricht, The Netherlands
2
Department of Medical Microbiology, NUTRIM – School of Nutrition and Translational Research
in Metabolism, Maastricht University Medical Center+, Maastricht, The Netherlands
3
Department of Medical Microbiology & Infection Control, VU University Medical Center,
Amsterdam, The Netherlands
Frank R. M. Stassen
[email protected]
In the respiratory tract, viruses and bacteria can interact on multiple levels. It is well known that
respiratory viruses, particularly influenza viruses, increase the susceptibility to secondary bacterial
infections. Numerous mechanisms, including compromised physical and immunological barriers,
and changes in the microenvironment have hereby been shown to contribute to the development
of secondary bacterial infections. In contrast, our understanding of how bacteria shape a
response to subsequent viral infection is still limited. There is emerging evidence that persistent
infection (or colonization) of the lower respiratory tract (LRT) with potential pathogenic bacteria,
as observed in diseases like chronic obstructive pulmonary disease or cystic fibrosis, modulates
subsequent viral infections by increasing viral entry receptors and modulating the inflammatory
response. Moreover, recent studies suggest that even healthy lungs are not, as had long been
assumed, sterile. The composition of the lung microbiome may thus modulate responses to viral
infections. Here we summarize the current knowledge on the co-pathogenesis between viruses
and bacteria in LRT infections.
Epidemiology and relevance of respiratory
co-infections
Co-infections of the lower respiratory tract (LRT) with
viruses and bacterial pathogens are commonly observed
during severe acute infections and in the course of chronic
respiratory diseases. In acute conditions, such as community-acquired pneumonia (CAP), mixed infections were
detected in up to 27 % of all cases in which a pathogen
could be identified (Bello et al., 2014). During exacerbations of chronic obstructive pulmonary disease (COPD),
potential pathogenic bacteria and viruses have been found
simultaneously in 12–25 % of the cases (Bafadhel et al.,
2011; Papi et al., 2006). Since many studies used conventional culturing techniques for detecting bacterial pathogens, rather than more sensitive molecular methods, the
true prevalence of mixed infections might even be
underreported.
It is increasingly recognized that the simultaneous presence of bacteria and viruses can affect the course and
severity of infections. Mixed infections have been found to
be associated with increased levels of inflammatory biomarkers such as procalcitonin and C-reactive protein during CAP (Bello et al., 2014) and have moreover been
linked to more severe exacerbations of COPD (MacDonald et al., 2013; Papi et al., 2006; Wilkinson et al., 2006).
Probably the most devastating example for a lethal viral/
bacterial synergism is the 1918/1919 influenza pandemic,
known as the ‘Spanish flu’. Most deaths during this largest
influenza pandemic of the 20th century are now believed
to have been a consequence of complications arising from
secondary bacterial infections, for example with Streptococcus pneumoniae or Staphylococcus aureus, rather than from
the virus alone (Morens et al., 2008).
The mechanisms leading to secondary bacterial infections
following antecedent viral infections have been extensively
investigated. In this context, particularly the co-pathogenesis of influenza viruses with bacterial infections has been
extensively investigated and has recently been reviewed by
McCullers (2014). In contrast, the role of other viruses,
as well the possible consequences of a preceding bacterial
exposure, e.g. in the form of acute and chronic infections
or as part of the microbiome, for secondary viral infections are less well understood. This review gives an overview of the current knowledge on the mechanisms
underlying bacterial–viral co-infections of the respiratory
tract, in either order of infection.
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000627 ã 2016 The Authors Printed in Great Britain
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Susceptibility and response to bacterial
infections following primary viral infections
Viral infections have been implied to affect the risk and outcome of bacterial infections via a number of mechanisms.
Broadly, these concern the epithelial barrier function and
binding of bacteria to the epithelium, innate and adaptive
immune response and the microenvironment of the LRT.
These aspects will be discussed in more detail below and are
summarized in Fig. 1.
Impairment of mucociliary clearance
the importance of the mucociliary escalator for bacterial
clearance, it is likely that reduced ciliary function hampers
bacterial clearance from the LRT.
Enhancement of bacterial binding
Viral infections can augment bacterial attachment and thus
help to establish bacterial infections. Increased attachment
of bacteria to virus-infected cells and tissue has been
observed for numerous combinations of respiratory pathogens, some of which will be discussed in more detail below
(Avadhanula et al., 2006; Golda et al., 2011; Hakansson
et al., 1994; Hament et al., 2004; Jiang et al., 1999; Raza
et al., 1993; Sanford & Ramsay, 1987; Wang et al., 2009).
Generally, bacterial attachment can be enhanced by (1)
increased expression of host receptors after viral infection
or (2) by viral structures serving as coupling agents for bacteria to host tissues.
The LRT is constantly exposed to small numbers of
microbes from the environment and the upper respiratory
tract, yet these bacteria usually do not persist in the LRT in
large numbers. Under normal conditions, inhaled particles
and infectious agents are trapped in mucus produced by
goblet cells and cleared from the airways by the coordinated
movement of cilia on epithelial cells.
During viral infections of the LRT, the production of mucus
is increased in order to facilitate viral clearance; excessive
mucus production, however, may contribute to airway
obstruction and impede mucociliary clearance (Vareille
et al., 2011). Viral infection can moreover cause a reduction
of ciliary beat frequency, uncoordinated ciliary movement
and a reduction in the number of ciliated cells (Chilvers
et al., 2001; Smith et al., 2014a; Tristram et al., 1998). Given
Receptor expression.
Among the host molecules upregulated on airway epithelial
cells upon viral infection, the platelet activating factor
receptor (PAFR) has been of particular interest. PAFR can
serve as an attachment molecule for S. pneumoniae, one of
the pathogens complicating influenza infection, as well as
for other phosphorylcholine-positive bacteria (Suri et al.,
2014). Moreover, PAFR expression is increased by
Effects during secondary
bacterial infection
Compromised barrier functions
- ↓ Mucociliary clearance, e.g. loss of ciliated cells, reduction of ciliary beat
frequency
- Loss of epithelial tight junction
Enhanced receptor availability for bacterial binding
- ↑ Expression of host receptors (e.g. PAFR)
- Display of viral proteins on the cell surface
Viral infection of the LRT
Immunological aberrances
- ↓ Expression and responsiveness of PRRs
- ↓ Numbers of alveolar macrophages, NK cells, CD4+ and CD8+ T-cells
- Impaired immune cell functions: ↓ Phagocytosis, cytokine, AMP and
antibody production
- Immunosuppression by viral components
Changes of the microenvironment
- ↑ Nutrient availability for bacterial growth
- ↑ Temperature and extracellular ATP altering bacterial transcriptome
Fig. 1. Effects of viral infections of the LRT on susceptibility and response to secondary bacterial infection. PAFR, Platelet
activating factor receptor; PRR, pathogen recognition receptor; AMP, antimicrobial peptides.
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Viral–bacterial interactions in the respiratory tract
inflammatory cytokines like TNF-a (Hinojosa et al., 2009),
in COPD lungs and after exposure to cigarette smoke (Shukla et al., 2016; Suri et al., 2014). Virus-induced upregulation of PAFR and concomitantly increased binding of
pneumococci and/or non-typeable Haemophilus influenzae
has been reported after infection with influenza virus (van
der Sluijs et al., 2006), human rhinovirus (HRV) (Ishizuka
et al., 2003), respiratory syncytial virus (RSV) and parainfluenzavirus (Avadhanula et al., 2006; Yokota et al., 2010).
While Avadhanula et al. (2006) found neutralizing PAFR
binding sites to reduce bacterial binding to RSV-infected
lung epithelial cells in vitro, the receptor’s relevance in vivo
during other viral infections is debated. Although pharmacological inhibition of PAFR did not reduce mortality in a
mouse model of co-infection with influenza and pneumococci, it modestly delayed mortality and clinical onset
(McCullers & Rehg, 2002). A study from the same group,
this time employing PAFR knockout mice, even found
increased mortality in co-infected PAFR / mice compared
with wild-type animals (McCullers et al., 2008). In contrast,
others reported reduced bacterial dissemination into the
circulation and decreased mortality in PAFR / mice
sequentially infected with influenza virus and S. pneumoniae
(van der Sluijs et al., 2006). Yet, the low survival rate and
the severity of the pneumococcal infection model make a
potential synergism of influenza virus and pneumococci in
this study difficult to appreciate. These diverging findings,
added to the fact that inhibition or deletion of PAFR cannot
entirely rescue the increased susceptibility to secondary
pneumococcal infection, indicate that co-pathogenesis of
influenza viruses and pneumococci is multifaceted.
Similar to PAFR, viral infection also changes the expression
of other transmembrane and extracellular matrix proteins
such as intercellular adhesion molecule (ICAM-1) or fibronectin. Influenza neuraminidase can activate latent transforming growth factor (TGF-b), which then mediates an
increase in the expression of a-integrins and fibronectin (Li
et al., 2015). Bacteria that bind the a-integrin/fibronectin
complex, such as H. influenzae, S. aureus and S. pneumoniae, can then increasingly attach to the respiratory epithelium. As shown by Passariello et al. (2006), the effects of
viral infection on receptor-mediated binding to epithelial
cells can be even more nuanced: although HRV infection
did not increase the adherence of S. aureus to lung epithelial
cells, it increased the efficiency with which bacteria were
internalized.
haemagglutinin into the cell membrane of infected cells
facilitates attachment and invasive disease of group A streptococci in mice (Okamoto et al., 2003). On top of this, the
binding of fibrinogen to cells infected with influenza A, and
the modulation of several surface molecules in influenzainfected cells is thought to aid the binding and invasion of
group A streptococci (Hafez et al., 2010; Sanford et al.,
1982).
Compromising the epithelial barrier function
Death of airway epithelial cells due to viral replication,
excessive inflammation and/or loss of repair functions can
damage the integrity of the airway epithelium (Herold et al.,
2008; Hinshaw et al., 1994; Kash et al., 2011; Schultz-Cherry
et al., 2001; Zeng et al., 2013). One consequence of this
compromised natural barrier can be invasive bacterial
infection.
Additionally, viruses can compromise the integrity of the
epithelial layer even in the absence of virus-induced cell
death. Sajjan et al. (2008) showed that infection of polarized
airway epithelial cells with HRV can lead to redistribution
of the tight junction protein zona occludens 1 (ZO-1) from
the membrane to the cytoplasm. Furthermore, HRV was
shown to impair the repolarization of airway epithelium
regenerating after injury (Faris et al., 2016). Integrity of the
epithelial barrier likewise is reduced after RSV infection
(Kilani et al., 2004). Increased release of vascular endothelial growth factor (VEGF) during infection hereby causes
gap formation between cells and thus decreased transepithelial resistance, a surrogate marker for epithelial barrier
function in vitro. Although the authors of this study did not
investigate to what extent this reduced barrier function
affects secondary bacterial infections, it is likely that bacterial transmigration is facilitated.
Immunological aberrances during postviral secondary bacterial infection
Increased bacterial binding and reduced barrier function
are important steps in initiating a secondary bacterial
infection. In combination with aberrant immune responses
due to viral infections, these can have devastating consequences. Immunologically, viruses alter the susceptibility
and responsiveness to bacteria on several levels of innate
and adaptive immunity.
Binding of bacteria to viral proteins displayed on the
host cell. Next to increased expression of host receptors,
Interference with pathogen recognition receptor
(PRR) expression and signalling
viral proteins displayed on the cell surface can enhance
adherence and internalization of bacteria. The RSV attachment glycoprotein (G) protein, present on the surface of
either RSV virions or infected cells, can serve as a binding
structure for non-typeable H. influenzae (Avadhanula et al.,
2007), S. pneumoniae (Avadhanula et al., 2007; Hament
et al., 2005) and Pseudomonas aeruginosa (Van Ewijk et al.,
2007). Similarly, integration of influenza virus
Sensing of conserved microbial structures by PRRs, such as
TLRs, is required for quick and efficient mounting of the
innate immune response. PRRs recognize diverse structures, yet the pathways triggered upon receptor activation
overlap and culminate in the activation of pro-inflammatory transcription factors (Kawai & Akira, 2011). To prevent over-activation, several feedback mechanisms are in
place, which can induce a refractory state to successive
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stimuli (Nahid et al., 2011; Neagos et al., 2015; de Vos
et al., 2009). If cells encounter multiple pathogens, this can
lead to a lack or delay in the response to secondary infection. Macrophages from influenza- or RSV-infected mice,
for example, are hypo-responsive to subsequent stimulation
with bacteria or bacterial mimics (Didierlaurent et al.,
2008). Astonishingly, this desensitization can be sustained
for weeks to months after the virus has been cleared. As a
consequence, neutrophil recruitment and bacterial clearance were found to be severely impaired in this study.
Similarly, HRV infection can blunt the TLR-dependent
response to bacterial challenge by causing degradation of
IRAK-1 (interleukin 1 receptor associated kinase), an adaptor kinase required for MyD88-dependent signaling (Unger
et al., 2012). This process renders pulmonary epithelial cells
less responsive to subsequent infection with non-typeable
H. influenzae and delays the innate response and bacterial
clearance. Because of the prolonged presence of bacteria,
the inflammatory response – once initiated – persists for a
longer period.
Immune cell function
As detailed below, viral infection can profoundly alter the
number and function of immune cells in the lung, further
delaying or hampering bacterial clearance.
Alveolar macrophages (AMs). AMs constantly sample the
alveolar lumen for foreign particles and not only serve in
bacterial clearance, but also secrete numerous cytokines and
chemoattractants to recruit immune cells to the site of
infection (Werner & Steele, 2014). In a murine model of
post-influenza pneumococcal pneumonia, Ghoneim et al.
(2013) observed an almost complete depletion of alveolar,
but not interstitial, macrophages following influenza infection. This effect was temporal, and interestingly, the highest
susceptibility to pneumococcal infection was in the time
frame of lowest numbers of AMs. Once the AM population
was restored, the susceptibility to pneumococcal infection
was indistinguishable to that of mice not infected with
influenza. Next to a depletion of AMs, influenza virus infection might also impair the cells’ phagocytic capacity (Jakab
et al., 1980; Warshauer et al., 1977). However, other studies
found no such impairment (Nugent & Pesanti, 1979) or
only impaired uptake of zymosan particles, but not of bacteria (Wang et al., 2012).
Unlike influenza, RSV and HRV do not or only limitedly
infect macrophages (Franke-Ullmann et al., 1995; Gern
et al., 1996), yet they can significantly influence number
and function of AMs. Impaired phagocytic capacity and/or
cytokine secretion after stimulation with bacterial products
have been reported for AMs and monocyte-derived macrophages following exposure to HRV and RSV (Arrevillaga
et al., 2012; Franke-Ullmann et al., 1995; Oliver et al., 2008;
Raza et al., 2000).
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Neutrophils. In contrast to AMs, neutrophils are not tissue
resident and need to be recruited from the bloodstream to
the site of infection (Werner & Steele, 2014). This recruitment requires adequate recognition of pathogens and
chemokine secretion by epithelial cells and macrophages. A
desensitization of AMs to pathogen-associated molecular
patterns (PAMPs) after viral infection (discussed above)
might therefore also reduce neutrophil recruitment. Mouse
models of secondary bacterial infections, however, point to
a functional impairment of neutrophils rather than solely a
lack of recruitment. Impaired bacterial clearance in influenza- or RSV-infected mice appeared to be related to
decreased activity of the antimicrobial enzyme myeloperoxidase and decreased production of reactive oxygen species
(LeVine et al., 2001; McNamee & Harmsen, 2006; Stark
et al., 2006). Additionally, increased levels of IL-10, as
observed during post-influenza pneumococcal pneumonia,
are thought to negatively affect neutrophil function (van
der Sluijs et al., 2004). Moreover, increased rates of neutrophil apoptosis have been observed after co-infection of
neutrophils with influenza and pneumococci in vitro (Colamussi et al., 1999; Engelich et al., 2001).
Another antimicrobial property of neutrophils is their ability to sequester pathogens in neutrophil extracellular traps
(NETs), which consist primarily of histones and DNA, but
also contain antimicrobial peptides (AMPs) (Kaplan &
Radic, 2012). Infection of neutrophils with RSV or influenza was found to enhance NET formation (Cortjens et al.,
2016; Narasaraju et al., 2011). But whereas superinfection
of influenza-infected mice with S. pneumoniae has been
shown to further increase the formation of NETs, these did
not confer protection against bacteria, due to partial
degradation and loss of antibacterial activity (Narayana
Moorthy et al., 2013). Prominent respiratory pathogens like
S. pneumoniae and S. aureus have furthermore developed
strategies to escape NET function (Beiter et al., 2006;
Berends et al., 2010), and in the context of co-infection,
increased NET formation might even contribute to airway
obstruction, hamper clearance mechanisms and aggravate
tissue damage, ultimately worsening the progression of secondary bacterial infections.
NK cells. NK cells can recognize viral structures on infected
cells and respond to stress signals released by the infected
host. They then contribute to antiviral immunity by killing
infected host cells, regulating T-cell function and secreting
interferon (IFN-g) (Hesker & Krupnick, 2013). NK cells
additionally contribute to clearance of pneumococcal infection through interaction with infected macrophages and
dendritic cells (Elhaik-Goldman et al., 2011; Hesker &
Krupnick, 2013; Mandelboim et al., 2001). Decreased numbers of NK cells in the lung and impaired NK cell function
after influenza infection of mice have been shown to impair
innate responses against S. aureus infection by contributing
to a lack of activation of AMs (Small et al., 2010).
Impairment of NK cell function has been observed for
numerous other viruses (Ma et al., 2016), although it is
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Viral–bacterial interactions in the respiratory tract
unclear to what degree this has consequences during
sequential infections of the respiratory tract.
Dendritic cells (DCs). As professional antigen presenting
cells, dendrtic cells (DCs) are at the interface between
innate and adaptive immunity in the lung, where different
DC subsets have distinct functions (Guilliams et al., 2013;
Hasenberg et al., 2013).
Co-infection of mice with influenza virus and Mycobacterium bovis has been found to reduce the expression of MHC
class I and II on DCs (Flórido et al., 2013). This, in turn,
impaired the generation of CD4+ and CD8+ T-cell
responses against the bacterium. Alternatively, in human
monocyte-derived DCs (moDCs), influenza virus has been
shown to increase TLR3 expression (Spelmink et al., 2016).
Although TLR3 is classically associated with the recognition
of viral structures (dsRNA), the authors of this study
showed that DCs also use TLR3 to recognize pneumococcal
RNA. In addition, the authors reported increased expression of IL-12p70 (Spelmink et al., 2016). Since IL-12 is an
important driver of T-helper (TH1) cell differentiation,
skewing of the TH cell population might contribute to the
outcome of co-infections.
Interference with DC function is not unique to infection
with influenza virus. RSV has been reported to render
moDCs less efficient in inducing CD4+ T-cell proliferation
and cytokine secretion by inducing the release of a soluble
mediator that is yet to be identified (de Graaff et al., 2005).
Although co-infections were not studied here, the secretion
of a soluble mediator affecting T-cell responses could have
implications for heterologous infections as well.
type II IFN (IFN-g). AMs respond to IFN-g with decreased
levels of the scavenger receptor MARCO, which is required
for uptake of non-opsonized pneumococci (Sun & Metzger,
2008). Since IFN-g is a common response to viral infection,
its inhibitory effects on antibacterial pathways are probably
not restricted to influenza virus infection, even though confirmation for other combinations of viruses and bacteria is
pending.
Taken together, there is compelling evidence for virusinduced impairments of the number and/or function of the
most important immune cell subsets in the lung. These
deficiencies take place on multiple levels and span cells of
both the innate and adaptive immune system, as well as
interactions between both.
Impairment of antibody-mediated immunity
The involvement of antibody-mediated immunity during
heterologous infections of the respiratory tract is largely
unknown, and outcomes of experimental studies are divergent. Whereas Wolf et al. (2014) described increased levels
of virus-specific IgG in a rather mild murine model of postinfluenza bacterial pneumonia, others found a severe
impairment of IgG, IgM and IgA production in co-infected
mice (Wu et al., 2015). These contrasting findings have
mainly been explained with differences in the experimental
models (sub-lethal vs lethal co-infection). The discrepancies
of these studies also highlight the influence of the choice of
experimental protocols and the need for further investigation to elucidate the precise contribution of antibody-mediated immunity.
Impairment of T-cell response. During viral infection, T-
cells have numerous functions, including the killing of
virus-infected cells by cytotoxic T-cells, and the activation
and control of various immune cells by TH cells. The role
of T-cells during respiratory infections has been extensively
reviewed by Chiu & Openshaw (2015). Several T-cell subsets have been implicated in aberrant immune responses
during post-influenza bacterial pneumonia. Blevins et al.
(2014) found that co-infection of influenza-infected mice
with S. pneumoniae affects the ongoing T-cell response to
the virus not only by reducing the number of virus-specific
CD8+ T-cells in the lungs, but also by reducing their cytokine production. Likewise, Wu et al. (2015) showed the
CD4+ T-cell population to be reduced during post-influenza pneumococcal infection. Moreover, influenza virus
infection has been demonstrated to impair the release of IL17 by TH17 cells and IL-17-producing gd T-cells during
secondary infection of mice with bacteria (Kudva et al.,
2011; Li et al., 2012). This aberrant production has been
attributed to deficient IL-23 production by DCs (Kudva
et al., 2011) and to suppressive effects of type I IFNs
released during primary viral infection (Li et al., 2012).
CD4+ and CD8+ T-cells can additionally contribute to
impaired initial clearance of bacteria by AMs by releasing
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Antimicrobial peptides
Antimicrobial peptides (AMPs) can be produced by most
cell types of the lungs, including epithelial cells, macrophages and neutrophils, and are effective against bacteria,
fungi and viruses (Lecaille et al., 2016). Expression of some
AMPs can be induced by infectious and inflammatory stimuli, which prompted researchers to investigate their role in
secondary infections. Experimental infection of COPD
patients with rhinovirus significantly increased the incidence of bacterial infections (Mallia et al., 2012). In those
COPD patients who also developed a secondary bacterial
infection, sputum levels of the protease inhibitors SLPI (serine leukocyte peptidase inhibitor) and elafin were
decreased. Interestingly, this decrease preceded peak bacterial loads, suggesting an involvement in the emergence of
secondary bacterial infections. Co-infection models of the
upper and lower respiratory tract with bacteria and, e.g.
RSV or influenza, support a role for the deregulation of
AMP production in facilitating secondary bacterial infection, yet the relative contribution of different AMPs and cell
types may vary per pathogen (Lee et al., 2015; McGillivary
et al., 2009; Robinson et al., 2014).
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Cytokines and other secreted mediators
During viral infection, production of type I and III IFNs
leads to expression of IFN-stimulated genes, which in turn
establish an antiviral state. While crucial for viral clearance,
the release of (particularly type I) IFNs appears to blunt several antibacterial responses by suppressing the expression of
AMPs, macrophage and/or neutrophil recruitment and
TH17 responses (Kudva et al., 2011; Lee et al., 2015; Nakamura et al., 2011; Shahangian et al., 2009). In contrast,
exogenous IFN-b was found to inhibit bacterial transmigration and thus to protect mice from developing bacteraemia
after instillation of S. pneumoniae, suggesting an ambiguous
role for type I IFNs during (secondary) bacterial infection
(LeMessurier et al., 2013).
Increased release of the anti-inflammatory cytokine IL-10
(along with a number of pro-inflammatory cytokines) during
co-infection of mice with influenza virus and pneumococci
has been implicated in an increased susceptibility to pneumococcal pneumonia. Neutralization of IL-10 reduced lethality
in co-infected mice, suggesting a prominent role for this cytokine in modulating anti-pneumococcal responses (van der
Sluijs et al., 2004).
In mice, increased levels of glucocorticoids following influenza infection have been linked to decreased control of Listeria monocytogenes during systemic bacterial infection
(Jamieson et al., 2010). Although surgical removal of the
adrenal gland could initially reverse the increased bacterial
burden in co-infected animals, these glucocorticoid-deficient mice, in contrast to sham-treated mice, eventually succumbed to co-infections, revealing an ambiguous role for
glucocorticoids during co-infections.
Overall, viral infections can influence the immune response
to subsequent bacterial infection on virtually all stages.
These immunomodulatory effects span pathogen recognition, innate as well as adaptive immune responses, and cellular functions and secretion of soluble mediators alike.
Other mechanisms
Immunosuppressive strategies of pathogens. Many
pathogens have evolved strategies to avoid the recognition
and clearance by their host’s immune system. Such immune
evasion largely interferes with recognition and the early, i.e.
innate, immune response. Considering that innate signalling responses to viruses and bacteria overlap, it is not surprising that immune evasion strategies not only affect
immunity against the primary pathogen, but also extend to
secondary infections.
Known suppressors of innate immunity are the RSV G protein or non-structural (NS) proteins of influenza, RSV and
other respiratory viruses (Arnold et al., 2004; Liu et al.,
2016; Polack et al., 2005; Zheng et al., 2015). In vitro, the
RSV G protein suppresses the inflammatory response of
several cell types to components of the virus itself, but also
dampens monocytic release of IL-6 and IL-1b upon stimulation with endotoxin. Influenza NS1 suppresses caspase-1
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activity, which is required for the release of IL-1b and IL-18
(Stasakova et al., 2005). Although the authors of this study
did not investigate the consequences of virus-induced caspase-1 inhibition on a heterologous infection, previous
studies have demonstrated a vital role of the caspase-1 system during bacterial infection (reviewed, for example, by
Netea et al., 2010), which suggests relevance for viral/
bacterial co-pathogenesis. Overall, the immunosuppressive
effect of NS1 extend to the expression of multiple cytokines,
likely contributing not only to impaired viral clearance, but
also to impaired responses to unrelated pathogens (Fernandez-Sesma et al., 2006). Additionally, the genome of most
influenza A isolates codes for the accessory protein PB1-F2,
a cytotoxin that worsens the outcome of secondary bacterial
infections with S. aureus and S. pneumoniae (Iverson et al.,
2011; McAuley et al., 2007).
Availability of nutrients and change of the microenvironment. By inducing changes in the microenvironment,
viruses can change bacterial growth patterns. Influenza neuraminidase cleaves sialic acid from sialylated airway mucins
enabling pneumococcal strains that are able to metabolize
these sugars to increase their rates of division (Siegel et al.,
2014). Moreover, elevated temperature and extracellular ATP
occurring during viral infection can trigger the release of pneumococci from biofilms and induce changes in the bacterial
transcriptome, associated with improved bacterial stress
responses, altered metabolism and increased virulence (Marks
et al., 2013; Pettigrew et al., 2014). Viral infections differentially impact the formation and maintenance of P. aeruginosa
biofilms: while the release of extracellular iron and transferrin
stimulates biofilm formation after RSV infection, the release of
hydrogen peroxide during HRV infection triggers the release
of P. aeruginosa and facilitates transmigration of bacteria
through the epithelial layer and might thus contribute to the
dissemination of infection (Chattoraj et al., 2011b; Hendricks
et al., 2016).
Influence of the bacterial microbiome and
bacterial exposures on viral infection
The presence of bacteria in the LRT was long considered to
be an abnormality associated with underlying chronic lung
diseases such as COPD, asthma or cystic fibrosis (CF). As
molecular techniques evolved, it became clear that conventional, culture-based techniques missed a substantial part of
the picture. Although bacterial loads decrease progressively
from upper to lower respiratory tract (Charlson et al.,
2011), bacterial genetic material has also been recovered
from the lungs of healthy individuals, leading to a reassessment of the paradigm of ‘sterile’ lungs.
Beneficial effects of a healthy respiratory
microbiome
The notion of a beneficial, healthy bacterial microbiome is
well established for the resident microbial community in the
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Viral–bacterial interactions in the respiratory tract
gastrointestinal tract, where resident bacteria aid in establishing a balanced immunological phenotype, compete with
‘invading’ (and potentially harmful) micro-organisms and
synthesize a variety of beneficial biomolecules, such as vitamins (reviewed, for example, by Kamada et al., 2013).
Although the bacterial load and species diversity in the
respiratory tract is substantially lower, similar beneficial
effects of a healthy pulmonary microbiome are under investigation, and first studies suggest a role for colonizing bacteria
in shaping the immune response to subsequent infection
(Fig. 2).
Excessive inflammation following viral infection significantly
contributes to airway pathology, thus a tolerance-inducing
microbiome might aid in limiting tissue damage. Colonization
of the upper respiratory tract with commensal bacteria has
been shown to drastically reduce influenza-induced acute lung
injury and mortality in mice by recruiting a CCR2+CD11b+
monocyte subset into the lungs and inducing a M2 macrophage phenotype (Wang et al., 2013). Strikingly, an intact
microbiome has also been shown to be required for the
formation of an adaptive response against influenza virus in
mice (Ichinohe et al., 2011). Mice treated with antibiotics
before influenza virus infection displayed lower antibody and
T-cell responses to the virus, thereby impairing virus clearance. Of note, this effect was not due to a general immune suppression, but specifically impaired adaptive immune responses
that require priming by an inflammasome – such as those to
infection with influenza viruses. Since the effects of antibiotic
treatment on bacterial communities are systemic and not
restricted to the respiratory tract, the relative contribution of
the respiratory microbiota to these findings is unclear.
Bacterial pathogens influencing the response to
viral infection
The few clinical studies that investigated the interplay
between bacterial colonization with potentially pathogenic
micro-organisms (PPMs) and viral infections of the respiratory tract, however, mainly relied on samples of the nasopharynx to determine microbiota composition, which are
not only significantly easier to obtain but also represent the
Effects during viral
infection
Bacterial exposure
Healthy microbiome
Promotion of
antibody generation
Pathogenic bacteria
Suppression of innate IFN
production due to e.g.
- PRR expression
- oxidative stress in
(CF cells)
Induction of an M2
phenotype in alveolar
macrophages
Modulation of
cytokine
expression
Expression of viral
entry receptors
Fig. 2. Effects of primary bacterial exposure on the response to respiratory viral infection.
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3095
C. Bellinghausen and others
main entry route for respiratory viruses. The most comprehensive studies on nasopharyngeal colonization and the risk
and severity of viral infections have been performed in
infants with RSV infection (de Steenhuijsen Piters et al.,
2016; Suarez-Arrabal et al., 2015). Children suffering from
RSV bronchiolitis were found more likely to be colonized
with PPMs. Moreover, the predominance of certain bacterial clusters could be linked to the severity of RSV bronchiolitis and to the host response, particularly to inflammatory
pathways. Similarly, nasal carriage of S. pneumoniae, but
not other PPMs, has been reported to be positively associated with rates of seroconversion to human metapneumovirus in children (Verkaik et al., 2011). Although a causal
relationship between nasopharyngeal colonization and the
response to viral infection cannot be deduced from these
studies, they suggest that microbiological phenotyping
might be predictive of the risk and response to viral infection. If a causality exists, a shift in the nasopharyngeal
microbiota caused by vaccinations against respiratory
pathogens would have implications for unrelated infections
as well (Biesbroek et al., 2014; Tarabichi et al., 2015).
Several studies have reported a persistent presence of PPMs
in the LRT of individuals with chronic pulmonary disease,
most prominently COPD (Cabello et al., 1997; Monsó et al.,
1999; Zalacain et al., 1999). Likewise, microbiome analyses
have revealed a change in microbial communities in the
LRT including a reduction in microbiome diversity and an
increased abundance of PPMs in subjects with COPD (ErbDownward et al., 2011; Garcia-Nuñez et al., 2014). Clinical
studies suggest an association between the presence of
PPMs in the stable state of COPD and chronic inflammation, a more rapid decline in lung function and an increased
risk for the development of acute exacerbations (reviewed,
for example, by Mohan & Sethi, 2015). Whether chronic
inflammation is a consequence of a afflicted microbiome or
vice versa remains to be investigated. Next to morbidity
associated directly with chronic bacterial infections, microbiome composition might also be linked to an altered risk
for (or outcome of) viral infections, which themselves are
considered important triggers of acute exacerbations
(Fig. 2). Exacerbations during which PPMs and viruses
were detected simultaneously were found to be on average
more severe (MacDonald et al., 2013; Papi et al., 2006; Wilkinson et al., 2006). Due to the design of these studies, it
cannot be said with certainty whether these events represent
a viral super-infection on top of bacterial colonization of
the LRT, yet this scenario appears to be more likely than a
simultaneous acquisition of two acute infections.
The co-pathogenesis of chronic bacterial and acute viral
infections might be explained by (1) a common underlying
factor that makes patients more susceptible to both types of
pathogens, e.g. compromised immune functions or
increased exposure, (2) an increased risk to acquire a viral
infection, e.g. due to the up-regulation of viral entry receptors, or (3) an altered response to viruses in patients with
chronic exposure to pathogenic bacteria, e.g. by synergistic
effects on inflammation or tissue damage. However,
3096
mechanistically, the question of how bacterial colonization
or chronic bacterial infection of the lungs affects the susceptibility to (and outcome of) subsequent viral infections has
rarely been addressed. The interplay between bacteria
classically associated with chronic lung diseases, such as
H. influenzae or P. aeruginosa, and respiratory viruses
hereby served as models.
H. influenzae is the most commonly found bacterial species
in the lungs of COPD patients, being cultured from samples
of about 25 % of all patients during stable disease (Cabello
et al., 1997; Monsó et al., 1999; Zalacain et al., 1999). Exposure of respiratory epithelial cells to H. influenzae increases
the expression of ICAM-1, the main receptor for major
group HRV. By doing so, the bacteria increase viral binding
and replication of this type of virus in vitro (Gulraiz et al.,
2015; Sajjan et al., 2006). Moreover, we have recently shown
that H. influenzae and RSV can synergize in inducing the
release of pro-inflammatory cytokines by respiratory epithelial cells (Bellinghausen et al., 2016). On the other hand,
TLR3 expression, and consequently recognition of viral
structures and antiviral type I/III IFN production, was
shown to be impaired in bronchial epithelial cells exposed
to Moraxella catarrhalis, another PPM commonly found in
the LRT of COPD patients (Heinrich et al., 2016). These
findings might, along with other factors, explain the
increased susceptibility of COPD patients to viral
infections.
CF patients are frequently colonized with P. aeruginosa
(Hector et al., 2016) and, like COPD patients, are prone to
develop exacerbations upon viral infection. Chattoraj et al.
(2011a) showed decreased production of type I and III IFNs
in CF cells exposed to P. aeruginosa and HRV compared
with cells exposed to HRV alone. This attenuation of the
antiviral response was reflected in higher viral titres. Infection with P. aeruginosa, however, did not affect the antiviral
response in healthy bronchial epithelial cells. Further analysis revealed that impaired production of antiviral mediators was linked to increased levels of oxidative stress in the
CF cells. Overall, however, the effects of preceding bacterial
exposures on subsequent viral infections remain insufficiently understood.
Direct interactions of bacteria and viruses:
altered virulence and structural
modifications
Although significant evidence for a direct interaction
between bacteria and viruses outside of laboratory conditions is still pending, there are intriguing experimental
studies showing that the co-pathogenesis of bacteria and
viruses might even start before infection (Fig. 3). Direct
binding of the RSV G protein to pneumococci induces
changes to the bacterial transcriptome and renders
bacterial strains more virulent by increasing the expression of virulence genes such as pneumolysin (Smith
et al., 2014b). Additionally, structural modifications might
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Journal of General Virology 97
Viral–bacterial interactions in the respiratory tract
influence pathogenicity of bacteria. Influenza virus neuraminidase, usually required for cleaving sialic acid groups
on host glycoproteins, can enzymically alter the structure
of sialic acid bearing capsules of certain meningococcal
serotypes (Rameix-Welti et al., 2009). These structural
modifications lead to enhanced bacterial adherence,
which may contribute to invasiveness.
Potential for clinical applications: innate
imprinting, prophylactic activation of TLR
signalling and manipulation of the
microbiome
Although inflammation-associated tissue damage contributes significantly to the pathology of infections, a temporary
augmentation of airway inflammation by administration of
aerosolized bacterial products has been suggested as potential prophylactic treatment during influenza epidemics.
Mice pre-treated with aerosolized bacterial lysates were
shown to mount an inflammatory response more rapidly
after influenza challenge, while at later stages of the infection local inflammation (and associated tissue damage) was
significantly decreased, as was mortality (Tuvim et al.,
2009). In a similar approach, activation of TLR2/6 and
TLR9 by pre-treatment with synthetic agonists reduced
parainfluenza virus titres in guinea pigs; however, this regimen was not able to prevent virus-induced airway hyperreactivity (Drake et al., 2013). Similar to the immunostimulatory effect of individual TLR agonists, innate immune
imprinting by local application of modified heat-labile
Escherichia coli toxins has been shown to confer protection
against respiratory viral infection in murine models (Norton et al., 2010; Williams et al., 2004). The need for local
application might even be circumvented by dietary intake of
probiotics, specifically those bacterial strains that trigger
type I IFN production by plasmacytoid DCs (Jounai et al.,
2015). Eventually, manipulation of the pulmonary microbiome may evolve as an alternative to the application of isolated microbial structures. However, for this approach to
succeed, a better understanding of what constitutes a
‘healthy’ microbiome is needed.
Next to the use of bacterial or viral structures to evoke
beneficial effects on the immune response to subsequent
infections, viral–bacterial interactions also have implications for treatment approaches using, e.g. adenoviral vectors, which might yield unwanted interactions between the
viral vector and subsequent infections (Brown et al., 2014).
General remarks
For the purpose of this review, we conceptually distinguished
between secondary bacterial and secondary viral infection.
Indeed, several studies point to distinct mechanisms of copathogenesis depending on the order of infection (Lee et al.,
2010; McCullers & Rehg, 2002). In the host, however, the
impact of sequential infections most likely does not stop
there, as acute exposures to pathogens have been shown to
trigger alterations in the local bacterial microbiome (Molyneaux et al., 2013; Tarabichi et al., 2015), which may impact
on subsequent ‘rounds’ of infection. Moreover, the pulmonary microbiome encompasses not only bacteria, but also
fungi and viruses (Marsland & Gollwitzer, 2014). Eventually,
it will not be sufficient to study microbial communities based
on their species composition, but rather on the level of a functional characterization.
We restricted this review to interactions of bacteria and
viruses during mixed infections, but cross-reactivity and copathogenesis is also observed during heterologous bacterial
infections (Ratner et al., 2005). Likewise, sequential infections with several viruses can negatively affect the host’s
immune response, whereas viral interference may prevent
or delay infection with a second virus (Casalegno et al.,
2010; Laurie et al., 2015; Nie et al., 2010; Welsh et al.,
2010). Moreover, interactions between fungi and viruses on
airway epithelial immunity have been reported, extending
this concept even further (Zhu et al., 2014). Finally, interactions are not restricted locally, but can be linked to systemic
or distal causes [e.g. general immunosuppression due to
human immunodeficiency virus (HIV)/AIDS and susceptibility to tuberculosis (Nunn et al., 2005), or immunomodulatory effects of helminths (Scheer et al., 2014)].
Conclusions
Direct interactions
between viruses and
bacteria
Structural modification
enhancing bacterial
attachment
Viral proteins as
coupling agents for
bacteria to the cell
surface
Changes in bacterial
transcriptome induced
by viral binding
Fig. 3. Direct viral–bacterial interactions of respiratory pathogens.
http://jgv.microbiologyresearch.org
Heterologous secondary infections can be facilitated by
various mechanisms, including a breach of barrier function,
profound immunological alterations, direct interactions of
pathogens and changes of the microenvironment. While
some of these mechanisms seem to apply to whole classes of
pathogens, others are highly pathogen specific. All these
aspects have primarily been investigated for viruses facilitating secondary bacterial infections, whereas the influence of
the respiratory microbiome on subsequent viral infection is
a relatively new, and hitherto neglected, concept.
To reveal functional consequences of an altered microbiome composition during viral infections, a better understanding of what constitutes a ‘healthy’ microbiome is
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3097
C. Bellinghausen and others
needed, which is currently hampered by the lack of large,
longitudinal studies. Ultimately, larger studies will also
be needed to identify interactions between different combinations of specific pathogens and to clarify whether chronic
bacterial exposures have clinically significant effects on the
outcome of viral infections.
Acknowledgements
We wish to thank Birke Benedikter (Department of Medical Microbiology, Maastricht University Medical Center+) for helpful discussions and critically reading the manuscript, and Mayk Lucchesi
(Department of Medical Microbiology, Maastricht University Medical
Center+) for the graphical design of the figures.
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