Orogastrointestinal Model of Mucosal and Disseminated Candidiasis
Animal models of infection are invaluable tools in studies of pathogenesis, immunological response, and for the testing of experimental therapeutics, which cannot be done in humans. Murine models of infection are used most often for these studies and prov
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1. Introduction Mucosal candidiasis is often associated with specific patient populations, particularly those that have an immunodeficiency, such as those with AIDS or cancer chemotherapy patients. Patients with AIDS show heavy colonization of the oral and esophageal mucosa, but dissemination to other body sites, and establishment of infection, from the mucosa occurs relatively rarely (1). In contrast, disseminated candidiasis occurs frequently in cancer chemotherapy
Alexandra C. Brand and Donna M. MacCallum (eds.), Host-Fungus Interactions: Methods and Protocols, Methods in Molecular Biology, vol. 845, DOI 10.1007/978-1-61779-539-8_41, © Springer Science+Business Media, LLC 2012
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patients and has been thought to arise as a result of translocation of the yeast from sites of mucosal colonization into the bloodstream (2, 3). A number of murine models of mucosal candidiasis have been described using immunodeficient SCID mice, antibiotic-treated mice, neonatal mice, and immunosuppressed mice (corticosteroid suppression, cyclophosphamide, methotrexate, etc.) (reviewed in (4–7)). Some reports of candidal gastrointestinal disease in mouse models mimicking that in cancer patients used neutropenia and immunosuppression to try to achieve dissemination, but used death as an end point. When we studied these, we found many of the deaths were due to disseminated bacterial infection. In our own work on antifungal therapeutics, we noted that suitable models for use in studies of antifungal treatment efficacy were lacking and worked to develop a standardized model of mucosal orogastrointestinal candidiasis due to Candida albicans that could be used for evaluating antifungal therapeutics. Because of the nature of the diseases in humans as described above, we developed two separate models of orogastrointestinal candidiasis. One model emulates patients with AIDS and is done using immunodeficient SCID mice (8, 9). In this model, no dissemination of C. albicans from the gut occurs. The second model standardized in our laboratory is one emulating neutropenic cancer chemotherapy patients and is done using immunosuppressed outbred mice (10). This model results in dissemination of C. albicans from the gut to the visceral organs and establishes stable colonization of the mucosal surfaces of the tongue, esophagus, stomach, small intestine, and cecum. Colonization and dissemination are demonstrable as early as day 3 postinfection, peaking between day 10 and 15 postinfection (10). We have used each of these models in preclinical drug trials and found them to have utility. Here we describe the performance of the model of mucosal candidiasis that results in dissemination of yeast from the gut to establish infection in the kidneys and liver. A broad-spectrum antibiotic regimen is initiated prior to infection and maintained for the duration of the experiment to reduce secondary bacterial infection that could interfere with subsequent results. Mice are immunosuppressed with weekly doses of 5-fluorouracil be
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