Project description:To mimic the initial phases of systemic Candida infections with dissemination via the bloodstream, we used an ex vivo whole blood infection model. Dual TP of C. auris in blood gave insights into fungal adaptations and survival mechanisms as well as the host response to the infection.
Project description:The ‘superbug’ Candida auris has been ranked as a priority fungal pathogen and is becoming a serious threat to public health. However, the underlying mechanisms of real-world pathogen-host interactions remain elusive, in part due to the lack of powerful immunocompetent animal models. In this study, we report that selected wild-type strains of Drosophila melanogaster can be developed as a promising infection model to recapitulate C. auris bloodstream infection. The systemic and organ-specific responses to C. auris infection in vivo were evaluated, as well as the corresponding transcriptional profiling. Our findings confirm that Toll and JAK-STAT signaling pathways mediate antifungal responses in the Drosophila model following C. auris infection. Moreover, we identified certain conserved novel factors required for host-C. auris interactions, highlighting the fly model's potential to reveal subtle immune mechanisms not readily observed in mammalian systems. Taken together, our work demonstrates that wild-type Drosophila offers a robust immunocompetent animal model for the further in-depth investigation of dynamic C. auris-host interactions in vivo.
Project description:The emergence of Candida auris poses a significant health challenge that has led to a new era of multidrug-resistant fungal infections. Invasive infections caused by C. auris are usually associated with remarkable morbidity and mortality. For many years, amphotericin B (AmB) remained the most efficient and the last line of treatment against most hard-to-treat fungal infections. However, strains of C. auris possess extraordinary resistance to most antifungal agents, including AmB. In this study, we screened ~2600 FDA-approved drugs and clinical compounds to identify the antiemetic drug rolapitant as a promising enhancer to AmB against C. auris. Rolapitant exhibited potent synergistic interactions with AmB against all tested (29/29) C. auris isolates. In a time-kill assay, rolapitant restored the fungicidal activity of AmB within 4 h. Additionally, the synergistic relationship between rolapitant and AmB was observed against other medically crucial Candida, Cryptococcus and Aspergillus species with ΣFICI that ranged from 0.16 to 0.5. In a transcriptomic study, ion transporters and ATP generation were identified as primary pathways impacted in C. auris AR0390 cells exposed to rolapitant. An ATP luminescence assay confirmed that rolapitant, at sub-inhibitory concentrations, significantly interfered with ATP production in C. auris. Moreover, rolapitant enhanced the in vivo activity of AmB in a mouse model of disseminated C. auris infection, as the combination reduced the fungal burden in murine kidneys by ~1 log (~90%) colony forming units. Our findings warrant further investigation of using rolapitant to overcome AmB resistance in C. auris and other fungal species.
