Respiratory syncytial virus activates Rab5a to suppress IRF1-dependent IFN-{lambda} production, subverting the antiviral defense of airway epithelial cells

Human respiratory syncytial virus (RSV) is a negative-strand RNA virus that causes severe acute pediatric respiratory tract infections worldwide. The limited effective antiviral options and lack of an effective vaccine against RSV highlight the need for a novel anti-viral therapy. One alternative is to identify and target the host factors required for viral infection. All viruses, including RSV, utilize cellular trafficking machinery to fulfill their life cycle in the infected host cells. Rab proteins mediate specific steps in intracellular membrane trafficking through the recruitment and tethering of fusion factors, and docking with actin- or microtubule-based motor proteins. Using RNA interference to knock down Rab proteins, we document that the micropinocytosis-associated Rab5a is required for RSV infection. RSV infection itself induces activation of Rab5a, and inhibition of this activation reduces RSV infection, but the mechanism for this effect remains unknown. Interferon (IFN) signaling plays an important role in innate immunity, and recent studies have identified IFN-λ (lambda), a type III IFN, as the most important IFN for antiviral immune in response to RSV infection of mucosal epithelium. However, how the RSV-induced Rab5a suppresses airway epithelial antiviral immunity has not been unraveled. Here, we show that activated Rab5a inhibits IRF1-induced IFN-λ production and IFN-λ-mediated signal transduction via JAK-STAT1, thereby increasing viral replication. Rab5a knockdown by siRNA resulted in stimulation of IRF1, IFN-λ and JAK-STAT1 expression, and suppressed viral growth. Our results highlight new role for Rab5a in RSV infection, such that its depletion inhibits RSV infection by stimulating the endogenous respiratory epithelial antiviral immunity, which suggests that Rab5a is a potential target for novel therapeutics against RSV infection.