Abstract
The thermally dimorphic fungus Paracoccidioides brasiliensis (Pb) is the causative agent of paracoccidioidomycosis (PCM), one of the most frequent systemic mycosis that affects the rural population in Latin America. PCM is characterized by a chronic inflammatory granulomatous reaction, which is consequence of a Th1-mediated adaptive immune response. In the present study we investigated the mechanisms involved in the immunoregulation triggered after a prior contact with cell-free antigens (CFA) during a murine model of PCM. The results showed that the inoculation of CFA prior to the infection resulted in disorganized granulomatous lesions and increased fungal replication in the lungs, liver and spleen, that paralleled with the higher levels of IL-4 when compared with the control group. The role of IL-4 in facilitating the fungal growth was demonstrated in IL-4-deficient- and neutralizing anti-IL-4 mAb-treated mice. The injection of CFA did not affect the fungal growth in these mice, which, in fact, exhibited a significant diminished amount of fungus in the tissues and smaller granulomas. Considering that in vivo anti-IL-4-application started one week after the CFA-inoculum, it implicates that IL-4-CFA-induced is responsible by the mediation of the observed unresponsiveness. Further, the characterization of CFA indicated that a proteic fraction is required for triggering the immunosuppressive mechanisms, while glycosylation or glycosphingolipids moieties are not. Taken together, our data suggest that the prior contact with soluble Pb antigens leads to severe PCM in an IL-4 dependent manner.
Highlights
Paracoccidioides brasiliensis (Pb) is a thermally dimorphic fungus that causes paracoccidioidomycosis (PCM), the most prevalent systemic mycosis in several countries of Latin America including Brazil, Argentina, Venezuela and Colombia
We first addressed the question if prior contact with cellfree antigens (CFA) provided protection against a subsequent P. brasiliensis infection
Our results showed the CFA-inoculated mice showed significantly higher number of yeast cells compared with PBS-injected mice
Summary
Paracoccidioides brasiliensis (Pb) is a thermally dimorphic fungus that causes paracoccidioidomycosis (PCM), the most prevalent systemic mycosis in several countries of Latin America including Brazil, Argentina, Venezuela and Colombia. Infection occurs by inhalation of fungal spores or particles, which transform into the pathogenic yeast form after reaching the pulmonary alveolar epithelium [3,4]. Classical studies demonstrated that benign forms of the disease are associated with low levels of specific antibodies and positive delayed-type hypersensitivity (DTH) reactions [9]. In this context, the resistance to fungal infections are related to T helper 1 (Th1)-type cytokines such as IL-12 and IFN-c, while susceptibility has been linked to the preferential production of the Th2 type responses, including IL-4, IL-5 and IL10 [10,11,12,13,14]. Several factors may contribute to this process, such as host and pathogen genetic background, fungal load and virulence [15,16,17]
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