Abstract
Immunostimulatory therapy is a promising approach to improving the treatment of systemic fungal infections such as paracoccidioidomycosis (PCM), whose drug therapy is usually prolonged and associated with toxic side effects and relapses. The current study was undertaken to determine if the injection of a T helper (Th) 1–stimulating adjuvant in P. brasiliensis–infected mice could have a beneficial effect on the course of experimental PCM. For this purpose, mice were infected and treated with complete Freund's adjuvant (CFA), a well-established Th1 experimental inductor, or incomplete Freund's adjuvant (IFA - control group) on day 20 postinfection. Four weeks after treatment, the CFA-treated mice presented a mild infection in the lungs characterized by absence of epithelioid cell granulomas and yeast cells, whereas the control mice presented multiple sites of focal epithelioid granulomas with lymphomonocytic halos circumscribing a high number of viable and nonviable yeast cells. In addition, CFA administration induced a 2.4 log reduction (>99%) in the fungal burden when compared to the control group, and led to an improvement of immune response, reversing the immunosuppression observed in the control group. The immunotherapy with Th1-inducing adjuvant, approved to be used in humans, might be a valuable tool in the treatment of PCM and potentially useful to improve the clinical cure rate in humans.
Highlights
Paracoccidioides brasiliensis is a thermally dimorphic human pathogenic fungus that causes paracoccidioidomycosis (PCM), the most prevalent human systemic mycosis in Latin America, being endemic in Brazil, Argentina, Venezuela and Colombia
We verified that a single-dose administration of an adjuvant that induces T helper (Th) 1 immune response in P. brasiliensis–infected mice was sufficient to break the lack of immune response to the fungus observed in infected mice
The CFA-treated mice presented a mild infection in the lungs characterized by preserved lung structure and small fungal burden, whereas control mice that had been treated with incomplete Freund’s adjuvant presented many granulomatous lesions and high fungal burden
Summary
Paracoccidioides brasiliensis is a thermally dimorphic human pathogenic fungus that causes paracoccidioidomycosis (PCM), the most prevalent human systemic mycosis in Latin America, being endemic in Brazil, Argentina, Venezuela and Colombia This infection is acquired by inhalation of airborne propagules found in nature, which reach the lungs and are converted to the yeast form [1,2]. Several investigators have suggested that progressive disseminated forms of PCM in humans are associated with various degrees of suppressed cell-mediated immunity [1,15,16]. This anergy can be reversed after successful therapy, when normal levels of T cell function are partially or completely restored [17]. The antifungal drugs most commonly used for PCM include amphotericin B, sulpha derivatives and azoles, but their
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