Evasion of type I IFN signaling by the small hydrophobic protein of HMPV and the implications for viral replication and pathogenesis
Hastings, Andrew Kenneth
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2015-03-26
Abstract
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.