The inflammasome potentiates influenza/Staphylococcus aureus superinfection in mice
Keven M. Robinson, Krishnaveni Ramanan, Michelle E. Clay, Kevin J. McHugh, Matthew J. Pilewski, Kara L. Nickolich, Catherine Corey, Sruti Shiva, Jieru Wang, Radhika Muzumdar, John F. Alcorn
Keven M. Robinson, Krishnaveni Ramanan, Michelle E. Clay, Kevin J. McHugh, Matthew J. Pilewski, Kara L. Nickolich, Catherine Corey, Sruti Shiva, Jieru Wang, Radhika Muzumdar, John F. Alcorn
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Research Article Immunology Pulmonology

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-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–/– mice are protected from bacterial superinfection and produce sufficient quantities of IL-1β through an apoptosis-associated speck-like protein containing CARD (ASC) inflammasome–independent mechanism. Despite the production of IL-1β 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-1β 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.

Authors

Keven M. Robinson, Krishnaveni Ramanan, Michelle E. Clay, Kevin J. McHugh, Matthew J. Pilewski, Kara L. Nickolich, Catherine Corey, Sruti Shiva, Jieru Wang, Radhika Muzumdar, John F. Alcorn

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Figure 5

Temporal NLRP3 inhibition enhances bacterial clearance but does not affect mortality during influenza and bacterial superinfection.

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Temporal NLRP3 inhibition enhances bacterial clearance but does not affe...
C57BL/6 and AIM–/– mice were infected with influenza A/PR/8/34 for 6 days, and then challenged with 108 CFU of methicillin-sensitive Staphylococcus aureus (MSSA) for 24 hours. (A) Bacterial colony counts in lung homogenate (n = 6). (B) Survival curve for WT and AIM–/– mice challenged with influenza followed by MSSA (n = 7–8). C57BL/6 mice were infected with 100 PFU of influenza A/PR/8/34 or vehicle for 6 days, and then challenged with 108 CFU of MSSA or vehicle for 24 hours. Mice received MCC950 5 mg/kg by oropharyngeal aspiration or PBS control on days 4 and 6 after influenza. (C) Bacterial colony counts in lung homogenate (n = 4 in MSSA-alone groups and 9–10 in Flu/MSSA groups). (D–F) Cytokine concentrations in lung homogenate as measured by Bio-Plex immunoassay (n = 9–10). (G) IL-1β concentrations in lung homogenate as measured by ELISA (n = 9–10). (H) Survival curve for WT and MCC950-treated mice challenged with influenza followed by MSSA (n = 8). *P < 0.05 versus Flu/MSSA by 1-way ANOVA or unpaired t test. Data points reflect individual values ± SEM. Each experiment was independently performed at least twice and data are shown from combined experiments with the exception of AIM–/– mouse data displayed in panel A and survival curves, which were performed once.