Host factors affecting susceptibility to Candida auris.

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This VA Merit research project aims to define host factors associated with mucosal infection by an emerging multi-drug resistant human fungal pathogen, Candida auris. Most human fungal infections are caused by Candida spp, the most common being C. albicans which colonizes approximately half of healthy adults. Pathological overgrowth can occur with perturbations to the commensal microbiota or host immunity and is normally limited to mucosal surfaces. However, bloodstream infections due to Candida spp. are common in healthcare settings and are associated with a high rate of mortality. Recently, the highly virulent strain Candida auris has emerged as an important healthcare-associated pathogen that has rapidly disseminated to multiple countries. This yeast is particularly concerning because it is often resistant to commonly used antifungal agents, with some strains exhibiting resistance to all currently available classes of antifungals (i.e., azoles, amphotericin B, and echinocandins). As of June, 2019, a rising number of clinical cases of C. auris have been reported in the United States, now over 700. Alarmingly, screening of close contacts in health care facilities shows that additional patients and care givers can be colonized with C. auris, showing the potential for widespread dissemination in healthcare settings. At this time, C auris outbreaks have just started to be detected in VA facilities. Based on the demographics of at risk patients (elderly, immunosuppressed, ICU or nursing home residents) and the rapid emergence of this pathogen in the US, it is likely just a matter of time before this emerging strain of Candida is more widely detected in veteran patient populations. To develop effective approaches to prevent transmission, there is an urgent need for studies that clarify the propensity for C. auris to colonize mucosal surfaces including the oral and intestinal tracts and to identify host factors that promote infection and overgrowth of this emerging pathogen. To date, few animal models of C. auris have been developed and currently there are no mucosal animal models of C auris infection or colonization. We have developed a novel mucosal model in which C. auris oral and gastrointestinal mucosal infection is observed as well as persistent shedding of the pathogen in stool. Our overall research goal is to define host factors including immune and microbiome profiles that alter susceptibility to Candida auris. In this project we plan to utilize our models of oral and GI infection to investigate the impact of factors such as antibiotic pre-exposure, alterations of the microbiome, and innate immune activation on infection with C. auris. We will utilize both in vitro and in vivo models to define critical innate immune receptors and pathways that impact mucosal infection with Candida auris. As many patients who are infected with C auris have previously received antibiotics to treat other infections, we will next determine the impact of antibiotic-induced alterations of the gut and oral microbiome on Candida auris infection. This project is highly significant given the rapid emergence of multi-drug resistant strains of Candida auris which poses a world-wide public health threat that also will likely impact Veteran’s health. Our project will advance our understanding of immune and systemic risk factors for infection with this pathogen, develop novel mucosal models of infection and study the impact of the microbiome on susceptibility to infection. Ultimately our goal is to help identify Veteran and other patient populations at highest risk for infection.