The unicellular parasite Trichomonas vaginalis is responsible for the most prevalent non-viral sexually transmitted infection worldwide, with approximately 170 million cases of trichomoniasis reported annually. In the US alone, the annual incidence is estimated at 3-5 million cases. In addition to infecting the human urogenital tract, trichomoniasis increases the risk of adverse pregnancy outcomes, HIV transmission and the incidence and severity of cervical and prostate cancers. It's prevalence and the recent increase in the number of drug resistant T. vaginalis strains underscore the need to develop new chemotherapeutic and vaccine design strategies. A much better understanding of processes involved in infectivity and pathogenesis, such as those proposed here, will be imperative to achieve these goals. We have discovered that T. vaginalis secretes small, membrane-bound vesicles, called exosomes, which are capable of fusing with and delivering proteins into the host cell. Parasite exosomes can also modulate host cell responses. The exosome-mediated host:pathogen interactions that we observed is an entirely new area of research that promises to uncover interesting, novel mechanisms. Our objectives are to further characterize exosome:host cell interactions and investigate the effect of exosomes on global host cell response. To this end, our studies will focus on characterizing exosomal fusion with host cells and exosome-mediated modulation of host cell gene and protein expression. The specfic aims of the proposal are:
Aim 1 : Determine whether the conserved exosomal membrane protein, tetraspanin 1, plays a vital role in exosome fusion with host cells and if this is mediate by selection of specific exosomal membrane-associated proteins.
Aim 2 : Determine whether exosomes from highly adherent and cytolytic T. vaginalis strains increase the ability of weakly adherent/cytolytic strains to adhere to and/or lyse vaginal epithelial cells. The exosomal proteomes of these strains will also be compared to identify candidate proteins involved in adherence and cytolysis.
Aim 3 : [Examine how] T. vaginalis exosomes modulate host cell responses by altering gene and protein expression in target human vaginal epithelial cells. These studies will greatly enhance our understanding of processes underlying the infectivity and pathogenesis of a prevalent human pathogen and have a high probability of revealing novel mechanisms used by the parasite to mediate host:pathogen interactions. As exosomes are also produced by mammalian cells and are known to play critical roles in both normal and pathological cellular functions, what we learn from the proposed studies is likely to also contribute to a better understanding of the role of exosomes in development, antigen presentation, immune modulation and cancer metastasis.
These studies will enhance our understanding of how a prevalent human pathogen establishes infection in its human host. The proposed research examines how cells communicate with each other using small vesicles that are produced by one cell and targeted to and fused with another. As exosomes are also produced by mammalian cells and play critical roles in both normal and pathological cellular functions, what we learn fro the proposed studies is likely to also contribute to a better understanding of mammalian development, antigen presentation, immune modulation and cancer metastasis.
|Riestra, Angelica M; Gandhi, Shiv; Sweredoski, Michael J et al. (2015) A Trichomonas vaginalis Rhomboid Protease and Its Substrate Modulate Parasite Attachment and Cytolysis of Host Cells. PLoS Pathog 11:e1005294|
|Twu, Olivia; DessÃ, Daniele; Vu, Anh et al. (2014) Trichomonas vaginalis homolog of macrophage migration inhibitory factor induces prostate cell growth, invasiveness, and inflammatory responses. Proc Natl Acad Sci U S A 111:8179-84|
|Leitsch, David; Janssen, Brian D; Kolarich, Daniel et al. (2014) Trichomonas vaginalis flavin reductase 1 and its role in metronidazole resistance. Mol Microbiol 91:198-208|
|Twu, Olivia; de Miguel, Natalia; Lustig, Gila et al. (2013) Trichomonas vaginalis exosomes deliver cargo to host cells and mediate hostÃ½Ã½Ã½parasite interactions. PLoS Pathog 9:e1003482|
|Lustig, Gila; Ryan, Christopher M; Secor, W Evan et al. (2013) Trichomonas vaginalis contact-dependent cytolysis of epithelial cells. Infect Immun 81:1411-9|
|de Miguel, Natalia; Riestra, Angelica; Johnson, Patricia J (2012) Reversible association of tetraspanin with Trichomonas vaginalis flagella upon adherence to host cells. Cell Microbiol 14:1797-807|