Human paracoccidioidomycosis: association study between cytokines genetic polymorphisms and immune responses on different clinical presentations of the disease

Abstract

Among the major endemical diseases in Latin America, paracoccidioidomycosis (PCM) stands out as a systemic granulomatous disease, caused by Paracoccidioides brasiliensis (P. brasiliensis). Inhalation of fungal conidia may result in asymptomatic infection, acute or chronic disease or sequelae. Murine model studies have established the role of innate and adaptative immunity and factors related to susceptibility and resistance both in resistant and susceptible mice against low and high virulent strains. In human PCM high levels of IFN-³ were associated with protection. However, the mechanisms determining evolution to infection or benign or severe disease are unknown. At the same time, and even though there are a number of studies suggesting a role of genetic inheritance in susceptibility/resistance to human PCM this role is not well understood. In this context, our work will investigate possible genetic determinants of the host (SNP - Single Nucleotide Polymorphism) and its influence over the immune response and clinical aspects of the disease. The objectives of the present study are: a) to identify the frequency and possible associations between genetic polymorphisms of IL-12p40, IL-12p70 e IFN-³, and receptors IL-12R²1 e IFN-³R1 in the different clinical forms; b) to investigate the possible association between genetic polymorphisms of IL-12p40, IL-12p70 e IFN-³, and receptors IL-12R²1 e IFN-³R1, and levels of IL-1², IL-4, IL-6, IL-10, IL-12p40, IL-12p70, IL-17A e IFN-³ in peripheral mononuclear cells cultures supernatants under P. brasiliensis antigen stimulus and in serum samples of patients with different clinical forms; c) to analyze the possible association between genetic polymorphisms of IL-12p40, IL-12p70 e IFN-³, and receptors IL-12R²1 e IFN-³R1 and different intracellular expressions of IL-1², IL-4, IL-6, IL-10, IL-12p40, IL-12p70, IL-17A and IFN-³ and extracellular expression of receptors IL-12R²1 e IFN-³R1 in peripheral mononuclear cells cultures under P. brasiliensis antigen stimulus of patients with different clinical forms of PCM. The results of this project could be useful for a better comprehension of the immunopathogenesis of PCM and could contribute for the management of patients with increased clinical expression of inflammatory lesions, possibly consequent to the host immune response to fungal antigens. (AU)