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Cytokines Expressed in the Granulomatous Lesions in Experimental Paracoccidioidomycosis: Role in Host Protective Immunity and as Fungal Virulence Factor

Eva Burger, Angela Satie Nishikaku, Jacy Gameiro, Carolina Francelin, Zoilo Pires Camargo and Liana Verinaud

Paracoccidioidomycosis (PCM) is a systemic granulomatous disease caused by the fungus Paracoccidioides brasiliensis (Pb). In the murine model of PCM, susceptible (S) mice develop disseminated disease with loose granulomas containing several viable fungi whereas resistant (R) mice show low fungal dissemination and encapsulated granulomas with few numbers of degenerated fungal cells. Here, we report the results of the expression of mRNA of these cytokines, as well as their distribution in the paracoccidioidomycotic granulomatous lesions and a semi quantitative score, that was correlated with the histological and biological data. Overall, our data show that the total area of granulomatous lesions and the relative areas of lesions containing Pb were, respectively, 1.2x and 1.9x more extensive in S than in the R mice. Also, the expression of IFN-γ and TNF-α mRNA was, respectively, 8x and 11x higher R mice and immunohistochemistry showed that the number of IFN-γ cells was 2.5x higher in R than in S mice. However, TNF-positivity was similar in the granulomas from S and R mice. In contrast, TGF-β mRNAs was 1.2x more expressed in S mice and this inhibitory cytokine was detected in higher concentration in the omental tissue from S mice.
We hypothesize that the infection of R mice by Pb leads to the preferential synthesis of TNF-α and IFN-γ that promote macrophage activation, probably enhancing Pb killing and control of fungal dissemination, in parallel with the development of compact granulomatous lesions containing few fungi. On the other hand, the infection of S mice elicits preferential synthesis of TGF-β that deactivates macrophages and may inhibit Pb killing by macrophages, favoring fungal dissemination and formation of loose granulomatous lesions. The positivity to TGF-β in Pb yeast cells may consist in a virulence factor of Pb, inducing the suppressive milieu that favors fungal dissemination.