Experimental Mouse Models of Disseminated Candida auris Infection.

Abstract

Disseminated candidiasis is a life-threatening disease and remains the most common bloodstream infection in hospitalized patients in the United States. Despite the availability of modern antifungal therapy, crude mortality in the last decade has remained unacceptably high. In particular, Candida auris is a multidrug-resistant, health care-associated fungal pathogen and has recently emerged as the first fungal pathogen to cause a global public health threat. A reliable animal model for disseminated C. auris candidiasis is therefore needed to study the unique aspects of this little-known host-pathogen interaction. In this study, we established an inbred A/J intravenous model as an appropriate model for human disseminated C. auris infection. We found that C5 deficiency in A/J mice results in a complex phenotype characterized by rapid fungal proliferation in target organs and the development of a unique and rapidly fatal response. In contrast, C57BL/6J mice and mice deficient in neutrophil elastase (NE-/-) survived high-dose C. auris intravenous challenge, even with cyclophosphamide (CY)-induced immunosuppression. Our study is the first to provide insight into the role of C5 in the host responses to C. auris invasive infection and establishes an inbred A/J mouse model of systemic C. auris infection without CY-induced immunosuppression.IMPORTANCE In the last decade, Candida auris has emerged globally as a multidrug-resistant fungal pathogen. Although C. auris was initially isolated from the external ear canal, it can cause outbreaks of invasive infections with very high mortality and comorbidities. Recent reports highlight the ongoing challenges due to organism misidentification, high rates of multifungal drug resistance, and unacceptably high patient mortality. The assessment of C. auris virulence in a specific genetic deficiency mouse model of invasive C. auris infection in this study contributes to the little knowledge of host defense to C. auris infection, which holds promise as a model for investigating the pathogenesis of C. auris invasive infection, exploring the immune responses elicited by the fungus, evaluating the possible induction of immunity to the infection, and targeting candidates for an antifungal vaccine.