Murine model of invasive pulmonary aspergillosis following an earlier stage, noninvasive Aspergillus infection

Abstract

Aspergillus spp. occasionally cause invasive pulmonary aspergillosis following noninvasive infection in patients with underlying bronchopulmonary disorders regardless of their systemic immunological conditions. We developed a murine model of invasive pulmonary aspergillosis following an earlier stage, noninvasive Aspergillus infection. BALB/c mice were inoculated intratracheally with agarose beads containing Aspergillus fumigatus conidia. Two weeks after inoculation, half of the mice were immunosuppressed with cortisone acetate. During a 4-week observation period, the survival rate of infected immunosuppressed mice was significantly lower (P < 0.01) than that of infected nonimmunosuppressed mice. The number of CFU in the lungs gradually decreased in the nonimmunosuppressed mice, whereas a time-related significant increase (P < 0.05) of CFU was demonstrated in the immunosuppressed mice. In the lungs of the nonimmunosuppressed mice, there was marked accumulation of neutrophils, lymphocytes, and macrophages (in this order) around the agarose beads in the bronchi. Aspergillus hyphae were surrounded by the inflammatory cells and did not invade the lung parenchyma. In contrast, in the immunosuppressed mice, Aspergillus hyphae proliferated markedly and invaded the lung parenchyma after immunosuppression. In this model, the two-dimensional extents of the lesions were also evaluated with an image-processing system. Time-related increase of the area of peribronchial necrotic lesions was significant (P < 0.05) after immunosuppression. This model should therefore be useful for investigating the pathophysiology of noninvasive Aspergillus infection and invasive pulmonary aspergillosis and also for clarifying the mechanism of conversion to the invasive disease from the noninvasive stage.