Mucosal Damage and Neutropenia Are Required for Candida albicans Dissemination

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Abstract
Candida albicans fungemia in cancer patients is thought to develop from initial gastrointestinal (GI) colonization with subsequent translocation into the bloodstream after administration of chemotherapy. It is unclear what components of the innate immune system are necessary for preventing C. albicans dissemination from the GI tract, but we have hypothesized that both neutropenia and GI mucosal damage are critical for allowing widespread invasive C. albicans disease. We investigated these parameters in a mouse model of C. albicans GI colonization that led to systemic spread after administration of immunosuppression and mucosal damage. After depleting resident GI intestinal flora with antibiotic treatment and achieving stable GI colonization levels of C. albicans, it was determined that systemic chemotherapy with cyclophosphamide led to 100% mortality, whereas selective neutrophil depletion, macrophage depletion, lymphopenia or GI mucosal disruption alone resulted in no mortality. Selective neutrophil depletion combined with GI mucosal disruption led to disseminated fungal infection and 100% mortality ensued. GI translocation and dissemination by C. albicans was also dependent on the organism's ability to transform from the yeast to the hyphal form. This mouse model of GI colonization and fungemia is useful for studying factors of innate host immunity needed to prevent invasive C. albicans disease as well as identifying virulence factors that are necessary for fungal GI colonization and dissemination. The model may also prove valuable for evaluating therapies to control C. albicans infections. Candida albicans is a fungus that lives harmlessly in the gastrointestinal (GI) tracts of humans. In cancer patients and patients undergoing bone marrow transplantation, however, the anti-cancer drugs that are administered to these patients also cause the undesired effect of suppressing the human immune system. The treatments allow C. albicans to spread into the blood and other organs and cause a severe disease. We found we could colonize the GI tracts of mice with C. albicans and then suppress the immune system with anti-cancer drugs to determine which components of the innate immune system (neutrophils, lymphocytes, macrophages, or GI tract integrity) are critical for preventing C. albicans from speading from the GI tract. We found that lowering the neutrophil counts and damaging the GI tract were both needed to cause systemic infection with C. albicans. We also found that the ability of C. albicans to switch from the yeast (spherical) form to the filamentous form is also important for establishing invasive disease. Our study provides new insights into the process of how a typically harmless microorganism inhabiting the GI tract can cause severe invasive disease once critical components of the host immune system are compromised.

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