Abstract
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.
Highlights
Paracoccidioidomycosis (PCM) is a systemic granulomatous disease, prevalent in Latin American countries, and whose causative agent is the thermally dimorphic fungus Paracoccidioides brasiliensis (Pb)
We proposed to study the participation of IFN-γ, TNF-α and TGF-β in the host-fungal interactions at the intimate site of the lesions by determining the expression of their mRNAs and their localization, as well as their concentration in culture supernatant of primary tissues, comparing this data with the architecture of the lesions developed in the omentum of resistant (R) and susceptible (S) mice to detect eventual differences due to the genetic background of the mice
The present work aimed to analyze the overall in situ participation of three cytokines (TGF-β, TNF-α and IFN-γ), in attempt to infer the consequences of their cooperative and antagonistic effects on the outcome of experimental paracoccidioidomycosis, using as a measure of control or progression of the disease the morphology of the granulomatous lesions, and the presence of P. brasiliensis with preserved or altered morphology. We correlate these findings with the expression of mRNA for these cytokines in granulomatous lesions, trying to assess parallelism between mRNA and protein synthesis
Summary
Paracoccidioidomycosis (PCM) is a systemic granulomatous disease, prevalent in Latin American countries, and whose causative agent is the thermally dimorphic fungus Paracoccidioides brasiliensis (Pb). PCM manifests in different clinical forms and may present as acute or chronic disease [1]. In the experimental murine model of PCM, previously described by our group [2], we demonstrated differences in susceptibility among inbred strains. Two strains of mice were shown to develop polar forms of the disease, A/Sn mice were resistant and B10.A mice susceptible to Paracoccidioides brasiliensis (Pb) infection [3]. The susceptible B10.A strain mice presented high fungal dissemination, as measured by the number of viable fungi found in the organs leading to high mortality. There was the formation of loose and disseminated granulomas, presenting innumerous multinucleated giant cells (MGCs), intense deposits of extracellular matrix (ECM) and numerous viable yeast cells, indicating progression and ineffective control of the disease. There was observed low activation state of phagocytes, high levels of specific antibody, suppressed delayed type hypersensitivity (DTH) and lymphoproliferative responses and a preferential Th2 cytokine production patterns, characterizing the anergic pole of the experimental disease [4]
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