Traffic of Leukocytes and Cytokine Up-regulation in the Central Nervous System in a Murine Model of Neuroparacoccidioidomycosis

Background: Paracoccidioidomycosis is the most important systemic mycosis in South America. In the last decades, it was observed that central nervous system involvement is frequent, occurring in 12.5 % of the cases. The aim of this study was to report the early inflammatory changes associated with an experimental model of neuroparacoccidioidomycosis (NPCM). Methods: C57BL/6 mice were infected by intracranial route with 10⁶ yeast cells of PB18 strain of Paracoccidioides brasiliensis. Leukocyte-endothelium interactions were assessed by intravital microscopy 1, 2, 4, and 8 weeks post-infection (p.i.). Chemokine/cytokine levels in the brain and histopathological changes were assessed 4 and 8 weeks p.i.. Results: Intravital microscopy analysis revealed a progressive increase in leukocyte recruitment in the vessels of pia mater with a peak 4 weeks p.i. The chemokine CXCL9 was increased at 4 and 8 weeks p.i., while CCL2, CCL3, and CCL5 were increased at 8 weeks p.i. Histopathological analysis revealed the infiltration of inflammatory cells and the development of progressive granulomatous meningoencephalitis. CCL3 levels correlated with clinical manifestations of disease, as measured by the SHIRPA battery. Conclusions: The experimental model of NPCM showed increased leukocyte recruitment associated with increased expression of chemokines and nervous tissue inflammation which correlated with clinical manifestations of disease.