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A6239 - The Inflammasome Potentiates Influenza, Staphylococcus Aureus Super-Infection in Mice
Author Block: K. M. Robinson1, K. Ramanam1, M. E. Clay2, K. J. McHugh3, J. F. Alcorn2; 1Medicine, University of Pittsburgh, Pittsburgh, PA, United States, 2Pediatrics, University of Pittsburgh, Pittsburgh, PA, United States, 3Pediatrics, University of Pittsburgh, Pittsburgh, PA, United States.
Rationale: Influenza is a common respiratory virus that results in up to 500,000 deaths worldwide each year. Influenza is often complicated by secondary bacterial infections of the lung, such as Staphylococcus aureus (SA). Secondary bacterial pneumonia is responsible for the severe morbidity and mortality observed during influenza infection. Influenza complicated by bacterial pneumonia is an effective model to study host defense during pulmonary super-infection due to its clinical relevance. Multi-protein 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 super-infection. Methods: Wild-type (WT) and ASC-/- mice were challenged with influenza A H1N1 (PR/8/34) followed by challenge with SA at 6 days post-influenza (model of super-infection). Next, WT and ASC-/- mice received a neutrophil elastase inhibitor, silvestat, or an IL-1R antagonist, anakinra, during super-infection. Finally, WT mice received the NLRP3 inhibitor MCC950 during super-infection. Bacterial burden, gene expression and cytokine production were measured. Results: We found that ASC-/- mice have decreased bacterial burden and improved survival compared to WT mice during super-infection. Further, ASC-/- mice produced sufficient quantities of IL-1β, but decreased pro-inflammatory cytokines compared to WT mice. Silvestat treatment decreased IL-1β production during super-infection and led to similar clearance of bacteria between WT and ASC-/- mice. Similarly, anakinra treatment resulted in similar clearance of bacteria between WT and ASC-/- mice. The administration of the inflammasome inhibitor MCC950 late in the course of influenza infection (days 5 and 6 post-infection) resulted in improved bacterial clearance and decreased inflammatory cytokine production compared to control mice. Conclusions: Our results demonstrated that IL-1β is necessary for the effective clearance of bacteria, but also contributed to excessive inflammation and mortality. We demonstrated that ASC-/- mice are protected from bacterial super-infection and produced sufficient quantities of IL-1β through an ASC inflammasome-independent mechanism. In addition, NLRP3 inflammasome inhibition later during the course of influenza infection, a scenario potentially most consistent with a clinical course, protected against bacterial super-infection.