Evasion of type I IFN signaling by the small hydrophobic protein of HMPV and the implications for viral replication and pathogenesis
Hastings, Andrew Kenneth
My thesis project explores mechanisms of innate immune evasion by human metapneumovirus (HMPV), as well as the consequences of a lack of type I IFN (IFNAR) signaling on host response and pathogenesis. I show that the expression of the small hydrophobic (SH) of HMPV inhibits type I IFN signaling through targeting signal transducers and activators of transcription 1 (STAT1). Next, I demonstrate that IFNAR signaling is important for the early control of HMPV replication and the development of functional CD8+ T cell (TCD8) response, but it also makes a significant contribution to disease pathogenesis. The effect on a functional T cell response depends on signaling in the bone-marrow compartment, while signaling on the lung epithelium drives pathogenesis. Additionally, the development of decreased functionality in IFNAR-/- mice correlates with expression of the inhibitory T cell receptor T cell immunoglobulin mucin-3 (TIM-3), and a greater ratio of alveolar macrophages to dendritic cells (DCs) early in infection. Taken together, I have revealed mechanisms by which HMPV is capable of evading type I IFN, and I have further elucidated the implications of IFNAR signaling evasion on the TCD8 response.