Identification of novel virulence factors and mechanisms of pathogenesis from the sexually transmitted protozoan Tritrichomonas foetus
Higgins, Melanie Rae.
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Tritrichomonas foetus (T. foetus) is the cause of trichomoniasis in cattle. Little is known regarding the basis of virulence in this parasite. Early host-parasite interactions most likely affect the ability of the parasite to colonize the female reproductive tract. These early interactions shape the course of disease and ultimately control the outcome of pathogenesis. The aim of the studies herein is to provide insight into the factors that alter the progression of trichomoniasis. We examined how environmental stress and estradiol treatment affect pathogenesis of trichomoniasis. Acute T. foetus infection in normal mice resulted in facile colonization of the reproductive tract with little epithelial damage, inflammation, or cytokine expression. Infection in estradiol-treated or stressed mice resulted in increased tissue damage, inflammation, and inflammatory cytokine expression. However, estradiol-treatment or stress did not result in enhanced T. foetus colonization within the reproductive tract. Since T. foetus has been associated with heavy neutrophil and macrophage accumulation in severe disease states, an additional goal was to examine the role of the innate immune system in the colonization of T. foetus within the murine reproductive tract. Mice depleted of neutrophils were more susceptible to infection than mock-depleted controls. Additionally, mice with deficiencies in RNS production had substantially larger parasite burdens than mice with the ability to generate RNS, whereas mice with the ability to generate ROS were equally able to control dissemination of T. foetus throughout the reproductive tract, compared to wild-type controls. Lastly, we examined the relationship between T. foetus and epithelial cell interactions to trichomonad virulence. Investigation of host-parasite interactions revealed that T. foetus exhibited increased adhesion and cytotoxicity towards host cells. In addition, a secreted cytoactive factor termed CDF was isolated and purified from activated parasites. This 30 kDa cysteine protease caused rounding and detachment of target cells in addition to inducing apoptosis and 100% cell death by 72 hours of exposure to target cells. These results support our hypothesis that initial parasite/host cell interactions affect trichomonad virulence.