Mechanisms of Candida auris skin colonization

点击翻译按钮获取中文摘要

ABSTRACT C. auris is a relatively new opportunistic fungal pathogen that is spreading worldwide with high rates of intrinsic resistance to antifungal antibiotics and a strong affinity for human skin. It is now ranked by the CDC as the top drug-resistant fungal threat. Epidemiological analysis suggests that pathogen transmission occurs efficiently in shared housing environments such as hospitals or nursing homes. Importantly, person-to-person transmission of skin-associated yeasts appears to be a primary mode of spread. Although C. auris skin colonization is asymptomatic, life-threatening disease can arise in patients with additional risk factors, such as immunosuppression, intravenous catheter placement, surgery, and antibiotics. Understanding of the molecular mechanisms by which C. auris tenaciously colonizes the skin might offer potential opportunities to interrupt the infection cycle. Unfortunately, no molecules been identified that are important for host skin colonization. To begin to address this problem, we have established three mouse models of skin colonization and epicutaneous infection with Candida albicans that are suitable for investigations of C. auris. Using these models, we observe significantly higher titers of C. auris than C. albicans. Unlike C. albicans, C. auris fails to induce skin damage or to induce expression of the key antifungal pro-inflammatory cytokine, IL-17. Notably, C. auris displays clusters of yeast in the epidermis as well as invasion of the hair follicles, neither of which are seen with C. albicans. In a forward genetic screen of ~700 C. albicans null mutants, we identified four genes required for epicutaneous infection of skin. We disrupted the C. auris orthologs using a CRISPR/Cas9-based protocol. We found that all four mutant displayed defects in skin colonization in C. auris. Notably, two of the four genes encode C. auris orthologs of components of the HOG MAP kinase signaling pathway and are required for effective skin colonization in all three models. These data lead us to hypothesize that the HOG MAPK signaling pathway controls skin colonization in C. auris by controlling the expression of downstream target genes. We hypothesize that one or more of these target genes will be involved in promoting the ability of C. auris to effectively colonize the skin. We will test this high-risk/high-payoff hypothesis by 1) Investigating the role of the C. auris Hog1 pathway in skin colonization and establishing its role in gene regulation and 2) Identifying effectors of C. auris skin colonization. These studies have the potential to identify molecules and mechanisms required for C. auris to colonize the skin, a central aspect of the infection cycle of this important emerging drug-resistant pathogen. Having laid the groundwork, we are in a strong position to accomplish these goals, which we anticipate will provide a foundation to begin to obtain molecular insights into the unique biology of C. auris.