Cromoblastomicose: à procura do modelo experimental murino. / Chromoblastomycosis: searching for experimental murine model.

Alexandre Paulo Machado

This study was prompted by the lack of a satisfactory chronic infection animal model for studies of experimental chromoblastomycosis and the fact that very little is known about the infective fungal forms of Fonsecaea pedrosoi. First, we investigated the infective potential of different mycelial forms of F. pedrosoi, hyphae, conidia and conidiogenous cells, in BALB/c mice. The extent to which each structure could survive the host tissue response was found to vary. In vivo transformation of the fungal inoculum into muriform cells was only observed when the mice were infected with conidiogenous cells. Neutrophils appeared to play an important role in the control of F. pedrosoi, possibly by degranulating and releasing toxic products, while macrophages may be of greater importance in clearance. Fungal inoculation of a single site led to an inflammatory response accompanied by the formation of abscesses rich in phagocytes. The fungus was eliminated efficiently in up to two months. However, antigenic co-stimulation with viable and nonviable fungal cells in two different sites, such as the footpad (s.c.) and peritoneum, led to the formation of multifocal lesions rich in histiocytes and to prolonged F. pedrosoi infection in different strains of mice and knockout animals. Clinical and mycological cure in these animals generally occurred after 4 months. When the primary focus in the co-stimulated animals (an abscess rich in neutrophils) disappeared, neutrophil migration to the secondary site (active multifocal lesions) increased, culminating in the elimination of the fungi. These data support the hypothesis that multifocal infections show individual immune responses, while systemic resolution of lesions is coordinated as a whole. After the mucosae had been immunized and footpads had been infected with F. pedrosoi cells, infectious lesions were found to be more prolonged, indicating that antigen presentation at different sites may be involved in peripheral tolerance mechanisms. Although lesions in co-stimulated CD4 KO mice worsened during the initial period following inoculation with the fungus, the mice were found to control the infection later. Exacerbated inflammatory progression and a worsening of the infection were observed in co-stimulated CD8 KO animals. Lesions in co-stimulated KO mice had a similar pathologic profile, but IL-10 KO animals did not developed prolonged infection after co-stimulation. Co-stimulated xid mice developed chronic infection, showing that B1 cells may have an antagonistic effect on the immunosuppressive response. In another study, we selected the bacterial strain B. subtilis, which has known antagonistic properties against filamentous fungi, for use in interaction assays with the F. pedrosoi strain. The main cell changes observed after co-culture were the transformation of hyphae into arthroconidial forms and the production of terminal chlamydoconidia. The induction of synthesis of fungal melanin was also observed. Fungal cells from co-cultures were inoculated into mice. The chlamydoconidia from these co-cultures were more resistant in vivo to the actions of phagocytes. In the final experiment, we used axenic F. pedrosoi cultures that had been maintained for six months. Various fungal forms, such as round cells and terminal and intercalary chlamydoconidia, with cell walls made up of multiple layers, were found in aged cultures. When inoculated into BALB/c mice, these fungal forms produced chronic infection, primarily in the group of animals infected at two sites. Our findings show that the development of a satisfactory murine model of chromoblastomycosis depends on factors associated with the parasite and the host. Potentially infective fungal cells should preferably be used when developing experimental models, and immunosuppression mechanisms such as antigenic costimulation should be used as auxiliary tools to increase the likelihood of obtaining chronic lesions in healthy animals.

Cromoblastomicose: à procura do modelo experimental murino. / Chromoblastomycosis: searching for experimental murine model.

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