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The inflammasome potentiates influenza/Staphylococcus aureus superinfection in mice.

ABSTRACT: Secondary bacterial respiratory infections are commonly associated with both acute and chronic lung injury. Influenza complicated by bacterial pneumonia is an effective model to study host defense during pulmonary superinfection due to its clinical relevance. Multiprotein inflammasomes are responsible for IL-1? production in response to infection and drive tissue inflammation. In this study, we examined the role of the inflammasome during viral/bacterial superinfection. We demonstrate that ASC-/- mice are protected from bacterial superinfection and produce sufficient quantities of IL-1? through an apoptosis-associated speck-like protein containing CARD (ASC) inflammasome-independent mechanism. Despite the production of IL-1? by ASC-/- mice in response to bacterial superinfection, these mice display decreased lung inflammation. A neutrophil elastase inhibitor blocked ASC inflammasome-independent production of IL-1? and the IL-1 receptor antagonist, anakinra, confirmed that IL-1 remains crucial to the clearance of bacteria during superinfection. Delayed inhibition of NLRP3 during influenza infection by MCC950 decreases bacterial burden during superinfection and leads to decreased inflammatory cytokine production. Collectively, our results demonstrate that ASC augments the clearance of bacteria, but can also contribute to inflammation and mortality. ASC should be considered as a therapeutic target to decrease morbidity and mortality during bacterial superinfection.

SUBMITTER: Robinson KM

PROVIDER: S-EPMC5928863 | biostudies-other | 2018 Apr

REPOSITORIES: biostudies-other

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The inflammasome potentiates influenza/Staphylococcus aureus superinfection in mice.

Robinson Keven M KM Ramanan Krishnaveni K Clay Michelle E ME McHugh Kevin J KJ Pilewski Matthew J MJ Nickolich Kara L KL Corey Catherine C Shiva Sruti S Wang Jieru J Muzumdar Radhika R Alcorn John F JF

JCI insight 20180405 7

Secondary bacterial respiratory infections are commonly associated with both acute and chronic lung injury. Influenza complicated by bacterial pneumonia is an effective model to study host defense during pulmonary superinfection due to its clinical relevance. Multiprotein inflammasomes are responsible for IL-1β production in response to infection and drive tissue inflammation. In this study, we examined the role of the inflammasome during viral/bacterial superinfection. We demonstrate that ASC-/ ...[more]

PMID: 29618653

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Project description:UnlabelledMuch of the morbidity and mortality associated with influenza virus respiratory infection is due to bacterial coinfection with pathogens that colonize the upper respiratory tract such as methicillin-resistant Staphylococcus aureus (MRSA) and Streptococcus pneumoniae. A major component of the immune response to influenza virus is the production of type I and III interferons. Here we show that the immune response to infection with influenza virus causes an increase and restructuring of the upper respiratory microbiota in wild-type (WT) mice but not in Il28r(-/-) mutant mice lacking the receptor for type III interferon. Mice lacking the IL-28 receptor fail to induce STAT1 phosphorylation and expression of its regulator, SOCS1. Il28r(-/-) mutant mice have increased expression of interleukin-22 (IL-22), as well as Ngal and RegIIIγ, in the nasal cavity, the source of organisms that would be aspirated to cause pneumonia. Proteomic analysis reveals changes in several cytoskeletal proteins that contribute to barrier function in the nasal epithelium that may contribute to the effects of IL-28 signaling on the microbiota. The importance of the effects of IL-28 signaling in the pathogenesis of MRSA pneumonia after influenza virus infection was confirmed by showing that WT mice nasally colonized before or after influenza virus infection had significantly higher levels of infection in the upper airways, as well as significantly greater susceptibility to MRSA pneumonia than Il28r(-/-) mutant mice did. Our results suggest that activation of the type III interferon in response to influenza virus infection has a major effect in expanding the upper airway microbiome and increasing susceptibility to lower respiratory tract infection.ImportanceS. aureus and influenza virus are important respiratory pathogens, and coinfection with these organisms is associated with significant morbidity and mortality. The ability of influenza virus to increase susceptibility to S. aureus infection is less well understood. We show here that influenza virus leads to a change in the upper airway microbiome in a type III interferon-dependent manner. Mice lacking the type III interferon receptor have altered STAT1 and IL-22 signaling. In coinfection studies, mice without the type III interferon receptor had significantly less nasal S. aureus colonization and subsequent pneumonia than infected WT mice did. This work demonstrates that type III interferons induced by influenza virus contribute to nasal colonization and pneumonia due to S. aureus superinfection.

Project description:Community interactions at mucosal surfaces between viruses, like influenza virus, and respiratory bacterial pathogens are important contributors toward pathogenesis of bacterial disease. What has not been considered is the natural extension of these interactions to live attenuated immunizations, and in particular, live attenuated influenza vaccines (LAIVs). Using a mouse-adapted LAIV against influenza A (H3N2) virus carrying the same mutations as the human FluMist vaccine, we find that LAIV vaccination reverses normal bacterial clearance from the nasopharynx and significantly increases bacterial carriage densities of the clinically important bacterial pathogens Streptococcus pneumoniae (serotypes 19F and 7F) and Staphylococcus aureus (strains Newman and Wright) within the upper respiratory tract of mice. Vaccination with LAIV also resulted in 2- to 5-fold increases in mean durations of bacterial carriage. Furthermore, we show that the increases in carriage density and duration were nearly identical in all aspects to changes in bacterial colonizing dynamics following infection with wild-type (WT) influenza virus. Importantly, LAIV, unlike WT influenza viruses, had no effect on severe bacterial disease or mortality within the lower respiratory tract. Our findings are, to the best of our knowledge, the first to demonstrate that vaccination with a live attenuated viral vaccine can directly modulate colonizing dynamics of important and unrelated human bacterial pathogens, and does so in a manner highly analogous to that seen following wild-type virus infection.Following infection with an influenza virus, infected or recently recovered individuals become transiently susceptible to excess bacterial infections, particularly Streptococcus pneumoniae and Staphylococcus aureus. Indeed, in the absence of preexisting comorbidities, bacterial infections are a leading cause of severe disease during influenza epidemics. While this synergy has been known and is well studied, what has not been explored is the natural extension of these interactions to live attenuated influenza vaccines (LAIVs). Here we show, in mice, that vaccination with LAIV primes the upper respiratory tract for increased bacterial growth and persistence of bacterial carriage, in a manner nearly identical to that seen following wild-type influenza virus infections. Importantly, LAIV, unlike wild-type virus, did not increase severe bacterial disease of the lower respiratory tract. These findings may have consequences for individual bacterial disease processes within the upper respiratory tract, as well as bacterial transmission dynamics within LAIV-vaccinated populations.

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The inflammasome potentiates influenza/Staphylococcus aureus superinfection in mice.

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The inflammasome potentiates influenza/Staphylococcus aureus superinfection in mice.

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