Invasive aspergillosis associated with prolonged leukopenia in a murine model

Objectives. Invasive pulmonary aspergillosis is the most important infectio n caused by filamentous fungus in patients, particularly those with prolong ed leukopenia. Despite numerous studies, the pathogenesis of invasive asper gillosis remains poorly understood. We propose a model of murine invasive p ulmonary aspegillosis occurring after intranasal instillation of Aspeugillu s fumigatus conidia in mice receiving repeated injections of cyclophosphami de. Our aim was to follow the progressive dissemination of the fungus from lungs in order to evaluate the extension of lesions inside the pulmonary ti ssue and to deep organs including kidney and brain. Materials and methods. Four different inoculum sizes (5 x 10(5), 10(6), 5 x 10(6) and 10(7):cfu) were used in mice and a profond leukopenia was strict ly maintained during the 22 days of the follow up by five repealed injectio ns of cyclophosphamide. Mortality rates, tissue burden and histopathologica l data have been collected from the four groups of mice. Results. Not surprisingly, the mortality rates of the groups of mice inocul ated with 5 x 10(6) and 10(7) cfu were significantly higher than those of g roups of mice infected with the two lower inocula. Nevertheless, in these t wo latest groups, Aspergillus hyphae was shown to proliferate and to invade the lung parenchyma and the blood vessels, and we observed pulmonary lesio ns and extrapulmonary dissemination. Conclusions. This experimental model of progressive invasive aspergillosis will provide new information concerning the factors involved in virulence o f Aspergillus spp. and the potential effect of various antifungal drugs on the evolution of the disease, including the modulators of the immune respon se.