Inflammasome Inhibition in Influenza A Virus Infected Juvenile Mice Leads to Improved Survival and Outcomes

Rationale Influenza A virus (IAV) is a highly contagious respiratory virus that infects up to 40% of children each year. Young children who progress to lower respiratory tract IAV infection are at risk of severe, life‐threatening disease. We previously demonstrated that viral clearance does not predict severity of illness in juvenile mice infected with IAV. Instead, excess activation of the NLRP3 (NLR family pyrin domain containing 3) inflammasome by IAV and the resultant cytokine storm are associated with increased lung injury in juvenile mice. Therefore, we hypothesized that inhibition of the NLRP3 inflammasome would protect juvenile mice from lethal IAV infection. Methods Juvenile mice (4 week‐old) were intratracheally infected with IAV (WSN 12.5 PFU). Two, three, and four days following infection, treatment with either an NLRP3 inflammasome inhibitor (MCC950) or saline control was initiated and continued until resolution of infection or death. Mice were evaluated for viral clearance and the development of acute lung injury. In addition, production of pro‐inflammatory cytokines, antiviral interferons and activation of the NLRP3 inflammasome were measured in bronchoalveolar lavage fluid (BALF). The immune cell profile was also evaluated in response to MCC950 treatment. Results Inhibition of the NLRP3 inflammasome with MCC950 3 days following infection protected juvenile mice from IAV‐induced lung injury and significantly increased survival. Earlier or later inhibition was not protective. Compared with vehicle‐treated controls, MCC950‐treated mice achieved an equal rate of viral clearance, but secreted decreased amounts of pro‐inflammatory cytokines. Further studies will be conducted to assess the effects on the immune cell population. Conclusion Modulation of the juvenile inflammatory response to IAV does not impair viral clearance. Instead, inhibition of excessive inflammation in juvenile IAV infection with a specific NLRP3 inflammasome inhibitor attenuates lung injury and improves survival in IAV‐infected juvenile mice. Our data suggest that therapies directed at the inflammatory response to IAV, and not viral clearance, warrant further investigation for treatment of severe IAV infection in children. Support or Funding Information HL128194 and HL071643