Development and validation of a localized murine candidiasis model : The pathogenesis, chemotheraphy and defense mechanisms to Candida mastitis in the lactating mouse

Sammanfattning: A murine model of localized candidiasis (mastitis) was developed. The model was analyzed withrespect to its discriminative abilities through investigation of the virulence properties of C.albicans mutant strains compared with the wild-type parental strain. Further validation of themodel was undertaken by assessment of pathogenesis, chemotherapy (amphotericin B andfluconazole) and complement activation using immunocompetent BALB/c mice, SCID andathymic nude mice. Six to eight week old mice were time mated. The pups were allowed to suckleup to day five post partum, at which time the lactating glands were inoculated with between 104 to109 cells of Candida. The animals were euthanized after 1-6 days of infection. The mammaryglands and several other organs were evaluated histopathologically. In the chemotherapy studies,the mammary glands were homogenized and fungal burden determined through culture of differentdilutions of the homogenate. Except in the very high inocula dose, the fungi were confined to themammary gland tissues. The infection remained localized and was most severe in SCID, followedby immunocompetent and athymic nude mice, in that order. The severity of pathological changes,which consisted of infiltration with neutrophils, necrosis and abscess formation, was exacerbatedby increasing the number of cells and/or the duration of infection in the untreated control animals.Animals infected with virulence factor knock-out strains showed reduced or no lesions while themajority of the animals infected with the wild-type strains showed severe lesions. In theamphotericin B treated animals, only mild pathological changes were seen compared to theinfected controls. Fluconazole treatment was ineffective in the treatment of mastitis. Complementfactor C3c levels were elevated and correlated to the severity of inflammation in all theexperiments and were significantly reduced by amphotericin B but not by fluconazole treatment.Conclusions: i) the murine mycotic mastitis is a discriminative model of localized candidiasis ii)severity of infection is dose- and duration-dependent iii) antifungal drugs can significantly reducefungal burden in the mammary gland and iv) there are other immune mechanisms that protect miceagainst dissemination of infection than T and B cell immunity.