Influenza A Virus Alters Pneumococcal Nasal Colonization and Middle Ear Infection Independently of Phase Variation

Wren, J. Thomas; Blevins, Lance K.; Pang, Bing; King, Lauren B.; Perez, Antonia C.; Murrah, Kyle A.; Reimche, Jennifer L.; Alexander-Miller, Martha A.; Swords, W. Edward

doi:10.1128/iai.01856-14

Cited by 27 publications

(37 citation statements)

References 63 publications

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“…Strikingly, even the carrier strain 19F caused severe disease and mortality following coinfection at a dose that was nonlethal in the absence of IAV infection in our model as well as in previously described studies (29,33). IAV infection has been shown to also support the development of otitis media by 19F (34,35). The strongest colonization was observed following monoinfection with 19F compared to T4 and 7F but without any apparent disease symptoms.…”

Section: Discussionmentioning

confidence: 51%

Influenza A Virus Infection Predisposes Hosts to Secondary Infection with Different Streptococcus pneumoniae Serotypes with Similar Outcome but Serotype-Specific Manifestation

et al. 2016

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e Influenza A virus (IAV) and Streptococcus pneumoniae are major causes of respiratory tract infections, particularly during coinfection. The synergism between these two pathogens is characterized by a complex network of dysregulated immune responses, some of which last until recovery following IAV infection. Despite the high serotype diversity of S. pneumoniae and the serotype replacement observed since the introduction of conjugate vaccines, little is known about pneumococcal strain dependency in the enhanced susceptibility to severe secondary S. pneumoniae infection following IAV infection. Thus, we studied how preinfection with IAV alters host susceptibility to different S. pneumoniae strains with various degrees of invasiveness using a highly invasive serotype 4 strain, an invasive serotype 7F strain, and a carrier serotype 19F strain. A murine model of pneumococcal coinfection during the acute phase of IAV infection showed a significantly increased degree of pneumonia and mortality for all tested pneumococcal strains at otherwise sublethal doses. The incidence and kinetics of systemic dissemination, however, remained bacterial strain dependent. Furthermore, we observed strain-specific alterations in the pulmonary levels of alveolar macrophages, neutrophils, and inflammatory mediators ultimately affecting immunopathology. During the recovery phase following IAV infection, bacterial growth in the lungs and systemic dissemination were enhanced in a strain-dependent manner. Altogether, this study shows that acute IAV infection predisposes the host to lethal S. pneumoniae infection irrespective of the pneumococcal serotype, while the long-lasting synergism between IAV and S. pneumoniae is bacterial strain dependent. These results hold implications for developing tailored therapeutic treatment regimens for dual infections during future IAV outbreaks. Infection with secondary bacterial pathogens is attributed to be the major cause of excessive mortality during influenza A virus (IAV) outbreaks. This lethal synergism has been recognized as early as during the 1918-1919 IAV pandemic with an estimated global death toll of 50 to 100 million (1, 2). Retrospective studies disclosed that 71% of the fatal cases during this pandemic were positive for Streptococcus pneumoniae (also called pneumococcus), providing the first epidemiological evidence for viral-bacterial coinfections (2). A clear predisposition to bacterial disease was also evident in all of the succeeding influenza pandemics, including the more recent 2009 H1N1 outbreak, which had a 10 to 55% higher incidence of hospitalizations and mortality due to bacterial pneumonia (3). Pneumococcal colonization is transient and asymptomatic in immunocompetent individuals and most commonly occurs in early childhood (4). At the same time, however, pneumococci are able to cause a variety of diseases ranging from mild sinusitis and otitis media to more-severe infections like sepsis and meningitis. Even though the introduction of the polyvalent pneumococcal conjugate vaccines...

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Section: Discussionmentioning

confidence: 51%

Influenza A Virus Infection Predisposes Hosts to Secondary Infection with Different Streptococcus pneumoniae Serotypes with Similar Outcome but Serotype-Specific Manifestation

et al. 2016

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“…When a weak biofilm-forming variant of S. pneumoniae was given alone, it displayed impaired colonization. However, when the weak biofilm variant was coinfected with influenza A, the investigators found increased biofilm formation and inflammation in the nasopharynx and middle ear [104]. While this is an excellent example of how a pre-existing viral infection can affect bacterial biofilm formation, there are very few animal models used to study viral-bacterial interactions.…”

Section: Otitis Mediamentioning

confidence: 99%

“…It is thought that upper respiratory viral infections, like those with influenza A virus, increase the chance of bacterial invasion into the middle ear and enhance virulence [103][104][105]. To investigate the interactions between viral and bacterial pathogens in upper respiratory infections, Wren et al infected mice intranasally with influenza A for 4 days, and then infected with S. pneumoniae.…”

Section: Otitis Mediamentioning

confidence: 99%

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Biofilm Models of Polymicrobial Infection

2015

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Interactions between microbes are complex and play an important role in the pathogenesis of infections. These interactions can range from fierce competition for nutrients and niches to highly evolved cooperative mechanisms between different species that support their mutual growth. An increasing appreciation for these interactions, and desire to uncover the mechanisms that govern them, has resulted in a shift from monomicrobial to polymicrobial biofilm studies in different disease models. Here we provide an overview of biofilm models used to study select polymicrobial infections and highlight the impact that the interactions between microbes within these biofilms have on disease progression. Notable recent advances in the development of polymicrobial biofilm-associated infection models and challenges facing the study of polymicrobial biofilms are addressed. Polymicrobial interactions in biofilmsOver the past 2 decades there has been a revolutionary paradigm shift in the field of microbiology with the appreciation that bacteria present in most biological systems exist in biofilms, rather than in a free-living state. This understanding has dramatically changed the way we study bacteria in the laboratory and resulted in the development of many new experimental systems that replicate biofilm environments [1][2][3][4][5]. Studies utilizing these systems have demonstrated time and time again that bacteria behave very differently when in a biofilm than during planktonic growth. In many ways, we now have to relearn everything we thought we knew about bacterial behavior through the view of the biofilm lens.Similarly, the recent explosion of metagenomic studies has significantly increased our appreciation of the complexity of the microbial populations present in biofilms [6,7]. This is also true for infections, most of which are thought to be biofilm related and inherently polymicrobial, including various species of bacteria, fungi and viruses [8]. It is thought that microbes act in concert to establish biofilms, which in turn can increase tolerance to antimicrobials, exacerbate of the host's immune response and increase persistence at the infection site [7,[9][10][11].Genetic diversity of microbes within biofilm communities is thought to increase the fitness of the residing community, making them more equipped to survive environmental stresses. In large part, this is due to an expanded gene pool, which can be more easily shared within the confines of a biofilm community [12]. Community composition and interactions within the community can have huge influences on bacterial behavior. Thus, just as the behavior of planktonic versus biofilm-associated bacteria is dramatically different, so is that of bacteria in single species versus multispecies systems.Interactions between microbes are complex and highly dependent on context. They can range from fierce competition for nutrients and niches, manifested by antagonistic behavior, to highly evolved cooperative mechanisms between different species that support their mutual grow...

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“…Left unclear, however, is the role of the pneumococcal neuraminidase NanA in this synergistic interaction, particularly as it relates to nasal colonization and middle ear infection. To assess this, we utilized a mutant strain of S. pneumoniae that does not express NanA in our previously established mouse model of S. pneumoniae and IAV coinfection (12). Our studies identified that prior IAV infection potentiates but cannot completely restore the ability of NanA-deficient pneumococci to cause nasal colonization and middle ear infection, suggesting that the activity of the viral neuraminidase was insufficient to fully complement the absent expression of NanA.…”

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confidence: 99%

Pneumococcal Neuraminidase A (NanA) Promotes Biofilm Formation and Synergizes with Influenza A Virus in Nasal Colonization and Middle Ear Infection

et al. 2017

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Even in the vaccine era, Streptococcus pneumoniae (the pneumococcus) remains a leading cause of otitis media, a significant public health burden, in large part because of the high prevalence of nasal colonization with the pneumococcus in children. The primary pneumococcal neuraminidase, NanA, which is a sialidase that catalyzes the cleavage of terminal sialic acids from host glycoconjugates, is involved in both of these processes. Coinfection with influenza A virus, which also expresses a neuraminidase, exacerbates nasal colonization and disease by S. pneumoniae, in part via the synergistic contributions of the viral neuraminidase. The specific role of its pneumococcal counterpart, NanA, in this interaction, however, is less well understood. We demonstrate in a mouse model that NanA-deficient pneumococci are impaired in their ability to cause both nasal colonization and middle ear infection. Coinfection with neuraminidase-expressing influenza virus and S. pneumoniae potentiates both colonization and infection but not to wild-type levels, suggesting an intrinsic role of NanA. Using in vitro models, we show that while NanA contributes to both epithelial adherence and biofilm viability, its effect on the latter is actually independent of its sialidase activity. These data indicate that NanA contributes both enzymatically and nonenzymatically to pneumococcal pathogenesis and, as such, suggest that it is not a redundant bystander during coinfection with influenza A virus. Rather, its expression is required for the full synergism between these two pathogens.

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Influenza A Virus Alters Pneumococcal Nasal Colonization and Middle Ear Infection Independently of Phase Variation

Cited by 27 publications

References 63 publications

Influenza A Virus Infection Predisposes Hosts to Secondary Infection with Different Streptococcus pneumoniae Serotypes with Similar Outcome but Serotype-Specific Manifestation

Influenza A Virus Infection Predisposes Hosts to Secondary Infection with Different Streptococcus pneumoniae Serotypes with Similar Outcome but Serotype-Specific Manifestation

Biofilm Models of Polymicrobial Infection

Pneumococcal Neuraminidase A (NanA) Promotes Biofilm Formation and Synergizes with Influenza A Virus in Nasal Colonization and Middle Ear Infection

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