Fungal virulence attributes and epithelial responses during vaginal Candida infections

Abstract

Candida species are constituents of the healthy human microbiota on the mucosal epithelial surfaces, such as the gut, oral cavity and vaginal tract. Although normally commensals, these yeasts can cause a wide variety of diseases, inlcuding vulvovaginal candidiasis (VVC). This is the second most common vaginal infection, affecting millions of women worldwide. In this thesis, the main focus was to dissect the interaction of vaginal epithelial cells with the four most prevalent human pathogenic Candida species. Using a time-course in vitro vaginal infection model, pathogenicity mechanisms of these Candida species were characterized. Comparative transcriptomics approach based on dual RNA-Sequencing indicated that these species exhibited species-specific transcriptional patterns, supporting the view that their virulence strategies have evolved independently. On the host side, an early response to all four species was characterized by a protective type-I interferon signalling induced via via transient host mitochondrial dysfunction. At later stages of infection, epithelial responses were driven by Candida species-specific capacities to inflict host cell damage. Moreover, the influence of host factors and a variety of newly synthesized compounds on Candida virulence properties was tested in the in vitro epithelial infection model and indicated their potential role during infection. Taken together, the results of this thesis provide new knowledge on Candida-epithelial interactions in the context of vaginal infections, both on the pathogen and the host side. The results are strengthened by extending the focus on the four most common Candida species, thus considering the evolutionary perspective of host-pathogen interaction. The described mechanisms may contribute to the development of novel diagnostic tools and immunotherapeutic applications.