ORCID
https://orcid.org/0000-0002-3271-5583
Date of Award
8-4-2023
Degree Name
Doctor of Philosophy (PhD)
Degree Type
Dissertation
Abstract
Genital Herpes Simplex Virus-2 (HSV-2) infections is a highly prevalent and incurable sexually transmitted disease. Upon infection at the primary genital mucosa, HSV-2 localizes to the sensory ganglia to establish chronic latency. Symptomatic and asymptomatic recurrences can then occur episodically to promote viral transmissions. Painful genital and peri-genital lesions can be formed, increasing the risk for secondary HIV-1 acquisition by three times. Despite being a serious public health risk with severe physiological and psycho-sociological impacts, there are currently no cures or FDA-approved vaccines for this chronic infection. Thus, it is imperative to understand how the immune system interacts with HSV-2 to enable us to develop better therapeutics and design new immunization strategies. Immunopathology. We used a female mouse model of primary infection to define immunopathogenic pathways. Our findings revealed that sustained type I interferon (IFN) signaling is a driver of pathogenic neutrophil responses, identifying Interleukin (IL)-18 as a novel component of disease during genital HSV-2 infection. We further show that IL-18 drives natural killer (NK) cells to produce the serine protease granzyme B. Accumulation of extracellular granzyme B in the vagina coincided with epithelial ulceration. Remarkably, genetic loss of granzyme B or therapeutic inhibition by a specific protease inhibitor was sufficient to reduce disease and restore epithelial integrity without altering viral control. Both IL-18 and granzyme B were markedly elevated in human herpetic ulcers compared to non-herpetic ulcers, suggesting these host mechanisms may be engaged in HSV-infected patients. Collectively, our study reveals that IL-18 induced by sustained type-I IFN signaling in neutrophils drive NK cells to promote granzyme B accumulation in the vagina, which in turn drives the destruction of vaginal epithelium during HSV-2 infection. Granzyme B is also identified as a novel therapeutic target to augment the treatment of genital herpes. Protection. Primary exposure to genital HSV-2 in humans and mice results in the development of vaginal tissue resident memory T cells (TRM). TRM-derived IFNγ was previously shown to drive viral clearance during subsequent viral exposure, likely acting through radio-resistant compartments. However, the downstream mechanisms and cellular targets of IFNγ remain elusive. To understand this, we immunized and challenged mice deficient for IFNγR either in the sacral ganglia, keratinocytes or myeloid compartments intravaginally with HSV-2, revealing that while peripheral neurons are not involved, IFNγ drives early viral clearance by acting on myeloid cells and later viral clearance via vaginal epithelial cells. Furthermore, IFNγ might be inducing inducible nitric oxide synthase (iNOS) expression, rather than TNFα, in myeloid cells for viral clearance. Taken together, we identified two distinct compartments as downstream targets of TRM-derived IFNγ which exhibit differential temporal kinetics in clearing secondary HSV-2 infection from the vaginal mucosa. Collectively, my thesis research has defined a complete pathway in which the immune system drives genital disease and tissue damage during primary infection, and also explored the immune correlates of protection during secondary infection with genital HSV-2.
Language
English (en)
Chair and Committee
Haina Shin
Committee Members
Deborah Lenschow
Recommended Citation
Lim, Ying Shiang, "Mechanisms of Immunopathology and Protection in Genital Herpes Simplex Virus 2 Infection" (2023). Arts & Sciences Electronic Theses and Dissertations. 3117.
https://openscholarship.wustl.edu/art_sci_etds/3117