Emerging Role of ZBP1 in Z-RNA Sensing, Influenza Virus-Induced Cell Death, and Pulmonary Inflammation

Influenza viruses cause respiratory tract infections, which lead to human disease outbreaks and pandemics. Influenza A virus (IAV) circulates in diverse animal species, predominantly aquatic birds. This often results in the emergence of novel viral strains causing severe human disease upon zoonotic transmission. Innate immune sensing of the IAV infection promotes host cell death and inflammatory responses to confer antiviral host defense. Dysregulated respiratory epithelial cell death and excessive proinflammatory responses drive immunopathology in highly pathogenic influenza infections. Here, we discuss the critical mechanisms regulating IAV-induced cell death and proinflammatory responses. We further describe the essential role of the Z-form nucleic acid sensor ZBP1/DAI and RIPK3 in triggering apoptosis, necroptosis, and pyroptosis during IAV infection and their impact on host defense and pathogenicity in vivo. We also discuss the functional importance of ZBP1-RIPK3 signaling in recent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and other viral infections. Understanding these mechanisms of RNA virus-induced cytopathic and pathogenic inflammatory responses is crucial for targeting pathogenic lung infections and human respiratory illness.