Anti-Human IAV H1N1/H3N2 chimeric monoclonal antibody, clone Ns20C0

Host innate immune system is critical for combating invading microbes including Influenza A virus (IAV). As an important arm of the innate immunity, the NLRP3 inflammasome has been found essential for protecting host against IAV challenge, while the mechanism remained elusive. Here we found that mice carrying a gain-of-function mutation in the Nlrp3 gene (Nlrp3(R258W)) are strongly resistant to IAV infection. Upon H1N1 IAV infection, the Nlrp3(R258W) mice exhibited decreased weight loss, increased survival rate and attenuated lung damage compared with WT littermate controls. Mechanistically, the resistance of Nlrp3(R258W) mice to IAV infection was dependent on IL-1 beta-mediated neutrophil recruitment. Upon IAV infection, mice carrying the Nlrp3(R258W) mutation produced more IL-1 beta than WT mice in the lung, which enhanced neutrophil recruitment locally. The recruited neutrophils facilitated IAV clearance, so that the viral load in Nlrp3(R258W) mice was lower than that in control mice. Conversely, neutrophil depletion in Nlrp3(R258w) mice compromised IAV clearance. Taken together, our results demonstrate a previously undescribed mechanism by which hyperactivation of the NLRP3 Inflammasome protects mice from IAV infection through IL-1 beta mediated neutrophil recruitment, thus suggest that positively fine tuning the physiological function of NLRP3 inflammasome can be beneficial for a mammalian host against IAV challenge.

The host cell protease TMPRSS2 cleaves the influenza A virus (IAV) hemagglutinin (HA). Several reports have described resistance of Tmprss2(-/-) knock-out (KO) mice to IAV infection but IAV of the H2 subtype have not been examined yet. Here, we demonstrate that TMPRSS2 is able to cleave H2-HA in cell culture and that Tmprss2(-/-) mice are resistant to infection with a re-assorted PR8_HA(H2) virus. Infection of KO mice did not cause major body weight loss or death. Furthermore, no significant increase in lung weights and no virus replication were observed in Tmprss2(-/-) mice. Finally, only minor tissue damage and infiltration of immune cells were detected and no virus-positive cells were found in histological sections of Tmprss2(-/-) mice. In summary, our studies indicate that TMPRSS2 is required for H2 IAV spread and pathogenesis in mice. These findings extend previous results pointing towards a central role of TMPRSS2 in IAV infection and validate host proteases as a potential target for antiviral therapy.