Candida auris extracellular vesicles subvert host immune responses

SUMMARY There are an ~150 deaths/hour due to mycoses. This underscores the knowledge gap in our understanding of the pathobiology of these predators, which is impeding our ability to more effectively combat invasive mycoses. We and others have demonstrated that extracellular vesicles (EV) are key modulators of the host immune response. The preliminary data for this R21 shows that C. auris EV directly and profoundly impede the activation of CD4+ T cells. The suppression of T cell activation may be an important facet in the explanation for C. auris' remarkable capacity to persist in the host. To more rigorously characterize this immunosuppressive interaction, we will robustly characterize the inhibitory effects and determine the mechanism(s) for this biological activity. The first Aim will define the inhibitory effect of EV from several C. auris strains on the activation of CD4+ and CD8+ T cells and determine the nature of the inhibitory compound(s). Our preliminary data shows that the presence of EV from C. auris significantly reduces pro-inflammatory cytokine secretion by activated CD4+ T cells and blocks proliferation of CD4+ T cells from activated OTII mice with an antigen presenting cell or directly, by the use of anti-CD3/anti-CD28 beads. We will also determine the nature of the inhibitory compound(s) packaged within the C. auris EV. The second Aim will define the mechanism(s) for the immunosuppressive effect of extracellular vesicles on T cells. We will identify which of the main pathways in T cells are altered by EV from C. auris through an examination of signaling from the upstream CD3 complex through to the transcription factors responsible for the polarization of T cell response towards different phenotypes, and we will characterize the cytokines secreted by these cells. Our preliminary data suggests that EV from C. auris have a direct effect on CD4+ T cells, which can bypass the antigen presentation step. Identifying the mechanism of action of EV along with the compound(s) responsible for the biological effects may have a marked impact on approaches to combatting fungal infections as well as addressing other diseases, such as autoimmune process.