ROLE OF THE NOVEL DNA SENSORS cGAS, IFI16, AND ZBP1, DURING VIRAL INFECTIONS IN GLIA

1 online resource (151 pages) : PDF

2020

University of North Carolina at Charlotte

Viral central nervous system (CNS) infections can lead to life threatening encephalitis and long-term neurological deficits in survivors. Resident CNS cell types, such as astrocytes and microglia, are known to produce key inflammatory and antiviral mediators following infection with neurotropic DNA viruses. However, the mechanisms by which glia mediate such responses remain poorly understood. Recently, a group of intracellular pattern recognition receptors (PRRs), collectively known as DNA sensors, have been identified in both leukocytic and non-leukocytic cell types. The ability of such DNA sensors to initiate immune mediator production and contribute to infection resolution in the periphery is increasingly recognized, but our understanding of their role in the CNS remains limited at best. There is evidence for the expression and functionality of DNA sensors in resident brain cells, and these molecules likely play a role in neurotropic virus infections. The DNA sensors cyclic GMP-AMP synthase (cGAS) and interferon gamma inducible protein 16 (IFI16) are two such sensors that have been reported to be important for recognition of DNA pathogens such as herpes simplex virus 1 (HSV-1) in peripheral human cell types. In this dissertation, we provide the first demonstration that human microglia and astrocytes show robust levels of cGAS and IFI16 protein expression at rest and following activation. Furthermore, we show that these cell types also constitutively express the critical downstream adaptor protein, stimulator of interferon genes (STING). Importantly, we demonstrate that, while cGAS serves as a significant component in interferon regulatory factor 3 (IRF3) activation and interferon beta (IFN-β) production by human microglial cell lines in response to foreign DNA, IFI16 is not required for such responses. Surprisingly, neither of these sensors mediate effective antiviral responses to HSV-1 in microglia, and this may be due, at least in part, to viral suppression of cGAS and/or IFI16 expression. As such, this ability may represent an important HSV immune evasion strategy in glial cells, and approaches that mitigate such suppression might represent a novel strategy to limit HSV-1 associated neuropathology.Finally, our group has demonstrated the functional expression of Z DNA binding protein 1 (ZBP1) in murine glia. We report that this sensor serves as a restriction factor for HSV-1 in both murine microglia and astrocytes. Importantly, we have begun to determine the antiviral mechanisms initiated by ZBP1 responsible for such restriction and we show that ZBP1 contributes to the activation of cell death pathways in glia following HSV-1 infection. Interestingly, while ZBP1 is best known for its role in the activation of necroptotic pathways our data suggests it also can contribute to apoptosis. Together, these data indicate that ZBP1 represents an important restriction factor for HSV-1 in glia and may be an ideal target for therapeutic intervention during HSE.

doctoral dissertations

Immunology
Virology
Neurosciences

Ph.D.

Astrocytes
CGAS
CNS
IFI16
Microglia
ZBPL

Biology

Marriott, Ian

Bost, Kenneth
Truman, Andrew
Grdzelishvili, Valery
Bennett, Jeanette

Thesis (Ph.D.)--University of North Carolina at Charlotte, 2020.

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Jeffries_uncc_0694D_12515

http://hdl.handle.net/20.500.13093/etd:1975