The inflammasome potentiates influenza/Staphylococcus aureus superinfection in mice
Keven M. Robinson, … , Radhika Muzumdar, John F. Alcorn
Keven M. Robinson, … , Radhika Muzumdar, John F. Alcorn
Published April 5, 2018
Citation Information: JCI Insight. 2018;3(7):e97470. https://doi.org/10.1172/jci.insight.97470.
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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 1

The ASC inflammasome promotes decreased bacterial clearance and increased mortality during influenza and bacterial superinfection.

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The ASC inflammasome promotes decreased bacterial clearance and increase...
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 methicillin-sensitive Staphylococcus aureus (MSSA) or vehicle for 24 hours. (A–C) Gene expression of inflammasome components in lung (n = 3–12). C57BL/6 and ASC–/– 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. (D) Bacterial colony counts in lung homogenate (n = 10–12). (E) Gene expression of influenza matrix protein in lung (n = 11–12). (F) Survival curve for WT and ASC–/– mice challenged with influenza followed by MSSA (n = 8). (G) C57BL/6 mice were infected with 100 PFU of influenza A/PR/8/34 or vehicle for 6 days, and then challenged with 5 × 107 CFU of methicillin-resistant S. aureus (MRSA) or vehicle for 24 hours (n = 12). *P < 0.05 versus naive WT by 1-way ANOVA; #P < 0.05 comparing SA with Flu/SA by 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 naive mouse data, which was performed once.