Aberrant RNA sensing and host-specific immunopathology in highly pathogenic influenza infections

Innate immune activation is critical for mounting protective host immune responses against viral infections. Viruses have evolved mechanisms to counteract host innate immune responses and restrict host defence. Intriguingly, growing evidence suggests that RNA viruses of zoonotic origin, particularly influenza viruses, trigger dysregulated innate immune activation leading to excessive inflammation and cellular damage. However, the host and viral mechanisms underlying the dysregulated innate immune responses that cause severe immunopathology remain to be fully unravelled. In this review, we discuss how aberrant RNA sensing contributes to innate immune responses during highly pathogenic influenza infections. We also discuss perspectives on influenza viral polymerase compatibility with host factors and species-specific RNA-sensing mechanisms as critical determinants of the pathological outcome during highly pathogenic influenza infections.