Candida albicans Colonizes and Disseminates to the Gastrointestinal Tract in the Presence of the Microbiota in a Severe Combined Immunodeficient Mouse Model

Candida albicans is the leading cause of candidemia or other invasive candidiasis. Gastrointestinal colonization has been considered as the primary source of candidemia. However, few established mouse models that mimic this infection route are available. In the present study, we established a mouse model of disseminated candidiasis developed through the translocation of Candida from the gut. In this study, we developed a novel C. albicans GI colonization and dissemination animal model by using severe combined immunodeficient Rag2(-/-)IL2 gamma c(-/-) (Rag2 gamma c) mice, which lack functional T, B, NK cells, and IL2 gamma c-dependent signaling. Rag2 gamma c mice were highly susceptible to C. albicans gastrointestinal infection even in the presence of the gut microbiota. Within 4 weeks post infection, Rag2 gamma c mice showed dose-dependent weight loss and disseminated candidiasis in more than 58% (7/12) of moribund mice. Histological analysis demonstrated abundant hyphae penetrating the mucosa, with significant neutrophilic infiltration in mice infected with wild-type C. albicans but not a filamentation-defective mutant. In moribund Rag2 gamma c mice, the necrotic lesions and disrupted epithelial cells were associated with C. albicans hyphae. Notably, removal of the gut microbiota by antibiotics exacerbated the severity of fungal infection in Rag2 gamma c mice, as demonstrated by elevated fungal burdens and accelerated weight loss and death. Furthermore, higher fungal burden and IL-1 beta expression were prominently noted in the stomach of Rag2 gamma c mice. In fact, a significant increase in circulating proinflammatory cytokines, including IL-6, TNF-alpha, and IL-10, indicative of a septic response, was evident in infected Rag2 gamma c mice. Additionally, Rag2 gamma c mice exhibited significantly lower levels of IL-22 but not IFN-gamma or IL-17A than wild-type B6 mice, suggesting that IL-22 plays a role in C. albicans gastrointestinal infection. Collectively, our analysis of the Rag2 gamma c mouse model revealed features of C. albicans gastrointestinal colonization and dissemination without the interference from antibiotics or chemotherapeutic agents, thus offering a new investigative tool for delineating the pathogenesis of C. albicans and its cross-talk with the gut microbiota.

Automated summary

This study established a mouse model of disseminated candidiasis developed through translocation of Candida from the gut, providing a new investigative tool for delineating the pathogenesis of C. albicans and its cross-talk with the gut microbiota. The model mimics the infection route of Candida and demonstrated features of gastrointestinal colonization and dissemination without interference from antibiotics or chemotherapeutic agents.