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.
Highlights
Candida albicans is a ubiquitous commensal organism that can cause serious disseminated infections in cancer patients [1,2]
We found we could colonize the GI tracts of mice with C. albicans and suppress the immune system with anti-cancer drugs to determine which components of the innate immune system 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
Summary
Candida albicans is a ubiquitous commensal organism that can cause serious disseminated infections in cancer patients [1,2]. Among the various invasive fungal infections reported in cancer patients, candidiasis is the most common infection (58%–69%) [5,6,7], and over the past decade, the incidence of invasive fungal infections in this population has increased significantly [8]. The presumed mechanism for all invasive C. albicans disease involves initial mucosal surface colonization followed by invasion into the adjacent tissues and organs. C. albicans usually colonizes the gastrointestinal (GI) tract with subsequent translocation into extraintestinal organs (i.e., mesenteric lymph nodes, blood stream, liver, and spleen) in the setting of chemotherapy-induced neutropenia and GI mucosal damage [9]. Common risk factors for developing candidemia in human patients include neutropenia, mucositis, use of broad spectrum antibiotics, and invasive medical procedures [6,12]
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