Changes in thymic microenvironment during the acute phase of experimental infection with Paracoccidioides brasiliensis

Paracoccidioidomycosis (PCM), a chronic disseminated fungal disease caused by Paracoccidioides brasiliensis (Pb) yeast cells, affects mainly rural workers but recently cases in immunedeprived individuals has risen considerably. Protective immune response against Pb is dependent on the activity of helper T cells, especially IFN-?-producing Th1 cells. In has been proposed that Pb is able to modulate the immune response towards a permissive state and that the thymus plays a major role. In this paper, we show that acute infection with Pb already provokes alterations in the thymic environment. We found that after seven days of infection, yeast cells were found on the thymic stroma and the expression of cytokeratins in thymic epithelial cells (TEC) were altered regarding their spatio-orientation. The absolute number of DPs and SPs thymocytes was reduced after seven days of fungal infection. Other changes were related to chemokine molecules that direct the migration of thymocytes, its expression was increased and consequently, thymocytes, the differentiating T cells, presented higher migratory ability in ex vivo experiments after seven days of infection. Notwithstanding, Pb-infected mice showed an increased frequency of prohibitive TCR-expressing T cells in the spleens, suggesting that the selection processes that occur in the thymus may be compromised in acute infection. We show for the first time that acute infection with Paracoccidioides brasiliensis yeast cells promotes thymic alterations leading to a defective repertoire of peripheral T cells. After 21 days of infection we find that our data returned to similar obtained in control mice. The data presented here may present new mechanisms by which Pb subverts the immune response towards the chronic infection observed in humans (AU)