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Saraph, Ananya

University of British Columbia

Sexually transmitted infections cause a large global health burden and disproportionately impact women. Herpes simplex virus-2 (HSV-2) and Zika virus (ZIKV) are sexually transmitted viruses that cause vaginal pathogenesis in women and can also harm fetal and neonatal health. There are currently no vaccines available against these viruses. There are no approved antivirals against ZIKV, and antivirals against HSV-2 cannot treat infection or prevent viral shedding, intensifying the need for novel therapeutics. There is also a lack of physiologically accurate in vitro models of vaginal infections that would improve our understanding of vaginal pathogenesis and contribute to the development of novel antiviral strategies. We have previously identified endogenous retrovirus (ERV)-mediated protection as a potential antiviral strategy against HSV-2. ERVs are “fossilized” remnants of germline infection and integration by ancient retroviruses that are implicated in human and health and disease, including protection against exogenous viruses. However, the mechanism of previously observed ERV-mediated protection against HSV-2 remains to be elucidated. My thesis aimed to address these gaps by accomplishing two main objectives: first, establishing a mouse vaginal organoid model of HSV-2 and ZIKV infection and second, using vaginal organoids and tail keratinocytes to investigate mechanisms of ERV-mediated protection against HSV-2. I hypothesized that vaginal organoids would support HSV-2 and ZIKV replication, and that both organoids and keratinocytes would show ERV-dependent restriction of HSV-2 in a cell-intrinsic manner. I found that vaginal organoids expressed markers of basal and apical differentiation, supported HSV-2 and ZIKV replication, and were capable of expressing interferon stimulated genes in response to interferon treatment. I also found that organoids and keratinocytes derived from mice with systemically elevated levels of ERVs could not restrict HSV-2 replication, thus ruling out cell-intrinsic resistance as a mechanism of ERV-mediated antiviral protection. Altogether, I was able to establish a novel, physiologically relevant, in vitro model of vaginal HSV-2 and ZIKV infection. This model of vaginal infection can be used in the future to model other vaginal pathogens, investigate mechanisms of vaginal pathogenesis, and develop novel therapeutic strategies against sexually transmitted infections.

Text

2024-10-21

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/89457

Microbiology and Immunology

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/