Immunomodulation of human paracoccidioidomycosis - evaluation of the effect of ArtimM lectin

Abstract

Infections caused by fungi are among the most life-threatening diseases. The paracoccidioidomycosis (PCM), caused by the fungus Paracoccidioides brasiliensis, is the most prevalent systemic mycosis in Brazil and the leading cause of death among immunocompetent individuals. Despite significant developments in antifungal chemotherapy, its efficacy remains limited since drug therapy is prolonged and associated with toxic side effects and relapses. Based on these data, there is a strong need for alternative or complementary clinical treatments to chemotherapy. The main clinical forms of PCM are: the acute/juvenile form (JF), which is characterized by systemic lymph node involvement, hepatosplenomegaly and bone marrow lesions. The JF form is characterized by predominant Th2 immune response. On the other hand, the chronic/adult form (AF) is localized and presents a high frequency of pulmonary, skin and mucosal involvement. It is characterized by a Th1 and Th17 immune response. Also, there is an asymptomatic infection observed in healthy individuals that do not develop clinical signs of disease; they develop a Th1 cellular immune response against fungal antigens. Therefore, these data support the idea that the response involved in the resistance to P. brasiliensis depends mainly upon a vigorous Th1-based, cellular immune response. ArtinM is a lectin from jackfruit seeds (Artocarpus heterophyllus) which acts in modulating immunity during experimental infections with several intracellular pathogens, including P. brasiliensis. Both prophylactic and therapeutic protocols of ArtinM administration to P. brasiliensis infected mice promote a Th1 immune response balanced by IL-10, which reduces the fungal load in organs of the treated mice while maintaining a controlled inflammation at the site of infection. This project proposes the study of the role of ArtinM lectin in the immunomodulation of human PCM. For that, we aim to verify the lymphoproliferative response and cytokine production by peripheral blood mononuclear cells, monocytes and neutrophils from PCM patients (AF and JF) and healthy controls. We will also verify the role of ArtinM on maturation of monocyte derived dendritic cells and activation of T cells. We believe that this study will collaborate to a better understanding of the immunopathology of PCM and also to identify new therapeutic strategies.