Hypoxic conditions promote Candida glabrata colonization in the intestinal tract and EPA6 plays a significant role in hypoxic adhesion to intestinal cells

Abstract

Candida glabrata, a fungal pathogen colonizing mucocutaneous membranes and indwelling medical devices, is associated with invasive infections, especially in immunocompromised individuals. Candidiasis could be of endogenous and exogenous origins. Endogenous infections are considered to derive from the invasion of Candida species colonizing the digestive mucosa. Investigations of the gut-to-bloodstream translocation mechanisms of Candida species remain limited, although environmental oxygen levels have been recently suggested to alter the human fungal pathogen phenotypes. Moreover, human fungal pathogens, including Candida, colonizing or invading less oxygenated tissues encounter altered oxygen circumstances. Therefore, phenotype investigation under hypoxic conditions could provide valuable novel insights into the host-pathogen interaction mechanisms. This study aimed to elucidate the adhesion capabilities and mechanisms of C. glabrata depending on various oxygen levels. We performed C. glabrata adhesion assays to Caco-2 cells under aerobic, microaerobic (5 vol% oxygen), and anaerobic conditions, conducted RNA-seq to identify candidate genes functioning on hypoxic adhesion. We then generated deletants of these genes and evaluated both their adhesion to Caco-2 cells under anaerobic conditions and their colonization ability in the hypoxic intestinal tract in a mouse model. We observed significant differences in Caco-2 cell adhesion in response to different oxygen levels. Under hypoxic conditions, the C. glabrata adhesion capability increased and the expression levels of seven adhesion-related genes were up-regulated. Among these mutants, the adhesion capability of epa6Δ decreased the most. The epa6Δ mutant exhibited significantly lower intestinal colonization in mice than the wild-type. To the best of our knowledge, this study first describes the hypoxic adjustment of C. glabrata to intestinal cell adhesion, in which EPA6 plays the most significant role. If Epa6p function could be inhibited, it may contribute to reducing endogenous infection. Phenotype investigation under hypoxic conditions could provide valuable novel insights into the host-pathogen interaction mechanisms.

The Hog1 MAPK substrate governs Candida glabrata-epithelial cell adhesion via the histone H2A variant

“…Cg is known to colonize caecum [55], and the lactate dehydrogenase CgCyb2 is required for survival in the caecum [52]. Cg adhered better to Caco-2 intestinal cells under hypoxia due to increased expression of the Epa6 adhesin, with Epa6 also being pivotal to mouse gut colonization [56]. Besides implicating CgHog1 in Cg survival in the host gut, our study provides the first line of evidence on how iron abundance impacts Cg colonization and intestinal survival.…”