Molecular regulation of host inflammation during influenza A virus infection (VIR5P.1155)

Abstract

Abstract The innate immune system recognizes influenza A viruses through multiple mechanisms, with recent studies revealing a critical role for the cytoplasmic NLRP3 inflammasome complex which promotes the maturation of the pro-inflammatory cytokine interleukin 1-β (IL-1β). Virus-induced NLRP3 inflammasome activation is critical for host defense and tissue repair during flu infection. Conversely, it is also evident that excessive NLRP3 inflammasome activity, especially during infection by highly pathogenic or pandemic strains of virus, can result in dysregulated inflammation that is detrimental to the host. Recent studies have identified a small molecule (pyrin-only protein 2 or POP2) that blocks the formation and activation of inflammasome complexes in humans. Because POP2 can interact with the pyrin domain of NLRP3, we hypothesize that POP2 functions to regulate the robust NLRP3-dependent IL-1β responses elicited during human IAV infection. Data from our continuing studies indicate that POP2 gene expression and function “cycles” with the expression of pro-IL-1β in PMA-differentiated human THP-1 monocytic cells exposed to seasonal and pandemic strains of influenza A viruses. Additionally, POP2 gene expression was found to be up-regulated in human donor PBMCs exposed to influenza A viruses. These findings support our notion that POP2 plays a critical role in ensuring a controlled, inflammatory response during human influenza A virus infection to favor protection over pathology.