ROLES AND REGULATION OF STAT3 IN INNATE IMMUNITY

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  • March 20, 2019
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  • Hsia, Hung-Ching
    • Affiliation: School of Medicine, Department of Cell Biology and Physiology
Abstract
  • Innate immunity is the first line of host defense to microbial infections. The rapid induction of the innate immune response is achieved through recognition of pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs). Upon recognition of PAMPs and DAMPs, cells initiate immune responses by expressing type I interferons (IFN) and interferon-stimulated genes (ISGs) to establish an antiviral and antimicrobial state, and by secreting cytokines and chemokines to recruit and activate immune cells such as macrophages and monocytes. These processes are precisely regulated to initiate a swift and effective defense against pathogens. My dissertation focuses on the roles and regulation of signal transducer and activator of transcription 3 (STAT3) in these responses. In the first project, I investigated the role of STAT3 in myeloid cells with regards to innate immune responses during viral infection. We discovered that STAT3 knockout mice are more susceptible to herpes simplex virus-1 (HSV-1) due to an attenuated IFN response and to defects in dendritic cell and natural killer cell activation, revealing a requirement of STAT3 in eliciting an effective innate immune response against HSV-1. The second project focused on dissecting the signaling pathways activated by cytosolic DNA, a DAMP, and the regulation of downstream transcription factors. I identified a novel signaling axis involving an inhibitory phosphorylation in STAT3 by TANK-binding kinase 1 (TBK1). This TBK1-mediated phosphorylation restricts STAT3 activation and expression of selective STAT3 target genes in response to cytosolic DNA. Collectively, the research presented in this dissertation demonstrates a pivotal role of STAT3 in host innate immunity against viral infection, and uncovers a novel mechanism whereby the activity of STAT3 can be fine-tuned by innate immune response pathways.
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  • In Copyright
Advisor
  • Damania, Blossom
  • Baldwin, Albert
  • Xiong, Yue
  • Cyr, Douglas
  • Major, Ben
Degree
  • Doctor of Philosophy
Degree granting institution
  • University of North Carolina at Chapel Hill Graduate School
Graduation year
  • 2017
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