Mechanism of Influenza Virus Induced Inflammatory Cell Death

Abstract

Abstract RNA viruses and host cell death responses are co-evolved which prompt the fate of immune responses. Inflammatory cell death is a form of programmed signaling cascade which lead to the loss of cell integrity and secretion of leaderless pro-inflammatory cytokines. Host innate immune system exerts inflammatory cell death to curtail virus replication and initiate protective inflammatory and adaptive responses. This also causes host tissue damage if uncontrolled. Elevated inflammatory responses and lung damage are primary causes for morbidity and mortality during pathogenic influenza infections. However, little is known about key mechanisms regulating influenza A virus (IAV) induced cell death and inflammation. We identified Z-DNA Binding Protein 1 (ZBP1) as a sensor of IAV infection to trigger inflammatory cell death in in vitro and in vivo. ZBP1 induced inflammatory cell death is specific to nuclear replicating IAV but not the other RNA viruses those replicate in the cytosol. We found that the ZBP1 translocate to the nucleus prior to the cell death execution. Unlike other innate receptors, ZBP1 recognizes unique patterns of RNA in ribonucleoprotein complexes (vRNPs) of IAV. This nucleate RHIM domain driven oligomeric RIPK3 signaling scaffolds to facilitate RIPK3-Caspase-8 dependent inflammatory cell death (both necroptosis and pyroptosis). Our biochemical studies identified RIG-I dependent activation, ubiquitination of ZBP1 and loss of mitochondrial integrity precedes inflammatory cell death which facilitate the assembly of cell death signaling complexes proximal to the cellular membrane. Overall, our work demonstrates the mechanism of sensing of nuclear replicating IAV vRNPs to trigger programmed inflammatory cell death.