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Title page for ETD etd-03172015-144524


Type of Document Dissertation
Author Hastings, Andrew Kenneth
Author's Email Address andrew.k.hastings@vanderbilt.edu
URN etd-03172015-144524
Title Evasion of type I IFN signaling by the small hydrophobic protein of HMPV and the implications for viral replication and pathogenesis
Degree PhD
Department Microbiology and Immunology
Advisory Committee
Advisor Name Title
Louise Rollins-Smith Committee Chair
John V. Williams Committee Member
Mark Denison Committee Member
R. Stokes Peebles Committee Member
Sebastian Joyce Committee Member
Keywords
  • STAT1
  • virus
  • human metapneumovirus
  • HMPV
  • typ I IFN
  • IFN
  • innate immunity
  • jak/stat
  • virus
  • IFN
  • interferon
  • T cell
  • inhibitory T cell pathways
Date of Defense 2015-03-09
Availability unrestricted
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.
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