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Title: | INVESTIGATING THE ROLE OF IL-17 IN MEDIATING ANTI-VIRAL T CELL IMMUNITY IN THE FEMALE REPRODUCTIVE TRACT DURING HSV-2 INFECTION |
Authors: | Bagri, Puja |
Advisor: | Kaushic, Charu |
Department: | Medical Sciences (Molecular Virology and Immunology Program) |
Publication Date: | 2020 |
Abstract: | Herpes simplex virus type 2 (HSV-2) is one of the most predominant sexually transmitted infections (STIs) in the world, with over 417 million individuals infected globally. Despite its widespread impact, there is still no cure or vaccine available for HSV-2. Rates of infection are higher in women compared to men, and the female reproductive tract (FRT) is the primary site of infection. Immune responses in the FRT are highly regulated by the presence of female sex hormones, and studies have shown that hormones can differentially affect susceptibility to infection. Our lab has been studying the effects of the hormonal microenvironment on genital HSV-2 infection for over a decade, and we and others have shown that the hormone estradiol (E2) is protective against HSV-2. Recent studies from our lab have reported that E2 appears to modulate CD4+ T cell immunity in the FRT, which is known to be critical for protection against HSV-2. In particular, E2 treatment resulted in robust IL-17+ CD4+ T cell responses, which coincided with enhanced Th1 immunity. While the protective anti-HSV-2 role of Th1 cells is well described in literature, little has been published on the importance of anti-viral Th17 immunity. The central objective of this dissertation was to further investigate the role of IL-17 in mediating anti-viral T cell immunity in the FRT during HSV-2 infection. We hypothesized that IL-17 enhances anti-viral protection against HSV-2 infection by mediating more efficient CD4+ T cell immunity in the FRT. First, we examined the importance of IL-17 during HSV-2 infection (Chapter 2). We showed that while IL-17 did not appear to play an important role during primary HSV-2 infection, it was critical for mediating protective immunity during the secondary recall response. We found that in the absence of IL-17, there was a compromised in vivo anti-viral Th1 recall response following intravaginal HSV-2 re-exposure and challenge, resulting in poor disease outcomes. These findings highlight a novel anti-viral role for IL-17 in the FRT, in which IL-17 mediates efficient Th1 immunity. Second, we examined the influence of IL-17 produced by innate sources, which represents the majority of IL-17 produced under homeostatic conditions, on the induction of T cell immunity in the FRT (Chapter 3). We found that in the absence of innate IL-17, vaginal dendritic cells were severely impaired at priming Th17 responses in vitro. Furthermore, this defect in Th17 induction was associated with reduced IL-1 production. We also characterized the primary source of innate IL-17 in the FRT and showed that γδ+ T cells were the predominant source of innate IL-17, and that these cells were modulated by both E2 and microbiota. These findings suggest that overall IL-17 production in the FRT is modulated by a variety of factors found in the local microenvironment, including innate sources of IL-17, E2 and the vaginal microbiota. Finally, we examined the effect of IL-17 and E2 on the establishment of memory T cells following HSV-2 immunization (Chapter 4). We found that following intranasal vaccination, E2 enhanced memory Th1 and Th17 populations in both the upper respiratory tract, as well as the FRT. In particular, E2 treatment resulted in greater establishment of vaginal CD4+ tissue-resident memory T (TRM) cells, a subset of memory cells known to be critical for protection against infection. Furthermore, we found that E2 enhanced vaginal Th1 TRM cells through an IL-17-dependent mechanism. These findings highlight a novel mechanism for E2-mediated protection against HSV-2 infection, in which E2 enhances the establishment of anti-viral CD4+ memory T cell populations during vaccination. This dissertation summarizes the original contributions and work completed during the last five years to understand numerous ways IL-17 influences anti-viral protection in the FRT. Taken together, these findings provide critical insight on prospective strategies to improve mucosal vaccines and generate more efficient protection against viral infections. |
URI: | http://hdl.handle.net/11375/25775 |
Appears in Collections: | Open Access Dissertations and Theses |
Files in This Item:
File | Description | Size | Format | |
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Bagri_Puja_202005_PhD.pdf | 9.15 MB | Adobe PDF | View/Open |
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