Date of Award
8-1-2024
Degree Name
Doctor of Philosophy (PhD)
Degree Type
Dissertation
Abstract
The complex interplay between aging, neuroinflammation, and neuroimmune responses has become increasingly evident in recent years. Microglia, the resident immune cells of the central nervous system (CNS), play a pivotal role in maintaining neural homeostasis and responding to neuroinflammatory triggers. This dissertation focuses on the role that aging plays in microglial activation and neuroinflammation, specifically in the context of West Nile Virus (WNV) encephalitis. While the incidence of WNV is consistent across age groups, the risk of West Nile Neuroinvasive Disease (WNND), a serious complication of WNV infection, increases with advanced age. Using mouse models of WNV infection, our group has shown that aged mice display significantly higher viral titers in both the periphery and the CNS. Aged mice are more susceptible to WNV infection and show alterations in both myeloid and lymphoid cell populations compared to younger infected controls. Specifically, aged microglia expressed lower levels of MHCII and higher levels of Programmed Cell Death Protein 1 (PD-1), while aged infiltrating WNV-specific CD8+ T cells exhibited reduced levels of interferon-gamma (IFNγ). We further explored the relationship between microglial senescence and antiviral response. Initially, we observed similarities between genes characterizing WNV-activated and aged microglia. These observations were confirmed using RNA sequencing of aged microglia and qRT-PCR and supplemented by spatial transcriptomics and flow cytometry to characterize changes in microglial gene signatures in adult and aged mice following recovery from WNV encephalitis. Our results show that WNV-activated microglia share transcriptional signatures with aged microglia, including upregulation of genes involved in interferon response and inflammation. Specifically, we focused on Lgals3bp, a heavily glycosylated protein expressed by a wide array of cells and present in most biological fluids. Although the exact functions of Lgals3bp are relatively unknown, it has reported roles in innate immunity, tumorigenesis, and potentially aging. Lgals3bp was broadly expressed in the CNS by microglia, astrocytes, neurons, and the ependymal cells of the choroid plexus. WNV infection significantly induced higher levels of Lgals3bp. We generated Lgals3bp-deficient mice, which exhibited higher weight loss after WNV infection compared to wild-type controls, albeit without a difference in survival or viral titers. These mice also had an increased number of microglia in the cerebral cortex, with a higher fraction of microglia expressing CD68, a marker of phagocytic activity. Additionally, these animals displayed increased CD4+ T cell numbers in the cerebral cortex during WNV infection. These findings indicate that LGALS3BP plays a role in regulating neuroinflammation and microglial activation. Targeting LGALS3BP may provide a potential route for mitigating neuroinflammation-related cognitive decline in aging and post-viral infections.
Language
English (en)
Chair and Committee
Robyn Klein
Committee Members
Erik Musiek; Geraldine Kress; Michael Diamond; Qingyun Li
Recommended Citation
Arutyunov, Artem D., "Aging Antiviral Immunity In The Central Nervous System: Mechanisms And Implications" (2024). Arts & Sciences Electronic Theses and Dissertations. 3281.
https://openscholarship.wustl.edu/art_sci_etds/3281