Genetic variation in the RSV fusion protein controls RSV strain-dependent inflammasome activation and the development of a pathogenic Th17 response

Abstract

Abstract Respiratory syncytial virus (RSV) is the leading cause of lower respiratory tract infections in young children worldwide. RSV-induced disease ranges from mild to severe, with severe disease correlated with elevated levels of pro-inflammatory cytokines, including the Th17-associated cytokine, IL-17. To better understand the viral factors that influence the induction of a Th17 response, we compared the inflammatory responses elicited by different RSV strains. In contrast to the commonly used RSV A2 strain, RSV 2-20 infection resulted in increased protein levels of IL-6 and IL-1β, which were required to induce a pathogenic Th17 response. RSV 2–20 infection increased mucus production and airway hyperreactivity indicating strain-specific disease induction. RSV 2–20 and A2 induced similar protein levels of caspase-1, however, 2–20 infection resulted in increased protein levels of pro-IL-1β suggesting differential activation of inflammasome signal 1. Increased production of IL-1β following RSV 2–20 infection was dependent on TLR4 expression and signaling, a canonical inflammasome signal 1 activator. A recombinant A2 virus expressing the 2–20 fusion (F) protein induced IL-1β to similar levels as wild-type 2–20 indicating the 2–20 F protein is sufficient to increase pro-inflammatory cytokine production. Reversion of three-point mutations in a region likely to interact with host cells in the RSV A2/2–20 F recombinant virus to the A2 sequence significantly reduced IL-6 and IL-1β protein production. Our results demonstrate that variation in the RSV F protein plays a crucial role in the induction of pro-inflammatory cytokines and modulating disease severity in the animal model and may contribute to differential RSV pathogenesis.