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PhD (Doctor of Philosophy)
Date of Award
Committee Chair or Co-Chairs
Michael Kruppa, J. Russell Hayman, Dennis Defoe, Douglas Thewke
The obligate intracellular bacterium, Chlamydia trachomatis, and Herpes Simplex Virus Type-2 (HSV-2) are the leading sexually transmitted pathogens in the world. These infections are usually asymptomatic and clinically mild, but complications can be severe. Reports of dual detection of Chlamydia and HSV within the genital tracts of humans led our laboratory to develop an in vitro Chlamydia/HSV co-infection model. Little is known regarding the specific pathogenesis of Chlamydia and HSV co-infections, but HSV-super-infection of Chlamydia-infected cells caused the chlamydiae to deviate from their normal developmental cycle into a non-replicative state termed persistence, or the chlamydial stress response. Interactions between HSV envelope protein, gD with host cell junction protein, nectin-1, were enough to stimulate the departure from normal chlamydial development. Additional data also suggested that there might be differences between single infection and co-infection outcomes in vivo. Thus, two diverging hypotheses were investigated here: i) that host nectin-1 is required for normal chlamydial development; and ii) that pathogen shedding and/or disease progression in Chlamydia and HSV-2 co-infected animals will differ from that observed in singly-infected animals. Chlamydial infection of nectin-1 knockdown cell lines revealed no inhibition of chlamydial entry, but significant reductions in inclusion size and production of infectious chlamydiae. Additionally, nectin-1 knockout mice shed fewer Chlamydia compared to wild type mice. In other studies, we developed a novel in vivo Chlamydia and HSV-2 intravaginal super-infection model in BALB/c mice. Infection with Chlamydia muridarum, followed up to 9 days later by HSV-2 super-infection, both reduced HSV shedding and protected mice from HSV-induced fatal neurologic disease compared to HSV singly-infected animals. Protection is lost when: i) infected animals are no longer shedding C. muridarum; ii) when mice are inoculated with UV-inactivated C. muridarum; or iii) when viable chlamydiae are eliminated from the genital tract using antibiotics prior to HSV-2 super-infection. Altogether, we have determined that host nectin-1 is required for chlamydial development both in vitro and in vivo, and that chlamydial pre-infection protects mice from subsequent HSV infection. We predict that these observations may lead to novel approaches to prevent human infection by these two common sexually transmitted pathogens.
Dissertation - Campus Only
Slade, Jessica A., "In Vitro and In Vivo Characterization of Chlamydia and HSV Co-infection" (2016). Electronic Theses and Dissertations. Paper 3026. https://dc.etsu.edu/etd/3026
Copyright by the authors.
Available for download on Friday, October 30, 2020