Immune Modulation by Exosomes in Trichomonas Vaginalis Infection

Exosomes and their microRNA cargo have been shown to modulate immune gene expression in the context of cancer; however, they are still a largely uncharted territory in the context of reproductive tract immunology. We used a human in-vitro model of the most common non-viral infection of the lower female reproductive tract caused by the protozoan parasite Trichomonas vaginalis (TV) to begin unveiling the role of exosomes in the host-microbe interactions in this anatomic compartment. We isolated exosomes from monocultures of different TV strains and from vaginal epithelial-TV co-cultures and investigated their effects on the acute immune response by bystander upper reproductive tract endocervical epithelial cells and peripheral blood mononuclear leukocytes (PBMC). It has previously been shown that TV carries endosymbiotic dsRNA Trichomonas vaginalis virus (TVV), which amplifies inflammatory responses to TV via TLR3 signaling.^ Our experimental data showed that the immuno-inflammatory effects of exosomes derived from TVV-positive parasites differ from those derived from TVV-negative parasites, including TVV-cured isogenic strains, suggesting a new role of the virus in the host-parasite interactions. The effects of exosomes derived from vaginal-TV co-cultures were also different from those from TV alone, suggesting a contribution of the human vaginal epithelium. Exosomes derived from TVV-uninfected or TVV-cured parasites but not from TVV-infected parasites activated NF-κB and induced selective proinflammatory cytokine expression in bystander endocervical epithelial cells. Similarly, in PBMC, exosomes from TVV- cured but not from the isogenic naturally TVV-infected parasites upregulated a myriad of proinflammatory cytokines.^ Exosomes from TV-infected vaginal cells suppressed cytokine upregulation induced via Toll-like receptor signaling and the suppression of proinflammatory cytokines was selectively and specifically induced when the parasites were TVV positive. The TV exosomes were also capable of abrogating T cell activation by IL-2/PHA as demonstrated by proportion of naïve CD4+CCR7+ cells. These findings suggest that the viral infection of the protozoan parasites affects the exosomal content and function and may serve to suppress human host immunity at the time of establishing the protozoan infection. The differential roles of protozoan and infected host exosomes in underlying inflammatory damage and reproductive outcomes require further studies.