Mechanisms of immunomodulation by ArtinM: basis for the development of new anti-fungal therapy

Abstract

Our group has evaluated the immunomodulation against pathogens by carbohydrate recognition on cell surface. We reported the ability of different lectins to modulate the immune system, as follows: mammal (Galectin-3), parasite (TgMIC1 and TgMIC4 from Toxoplasma gondii), fungus (Paracoccin from Paracoccidioides brasiliensis), and plant (ArtinM from Artocarpus heterophyllus). ArtinM showed important immunomodulatory activity that is associated with Th1 immune response, which is triggered by ArtinM binding with TLR2-N-glycans. The ArtinM immunomodulatory activity utilizes the IL-12 production by macrophages and dendritic cells. Moreover, ArtinM interacts with CXCR2 on neutrophils, FcµR on mast cells, and CD3 on lymphocytes; the ArtinM binding with different cells favors a protective immune response against intracellular pathogens. Considering the ArtinM effects is essential to study the mechanisms involved in the immunomodulation triggered by ArtinM on immune cells. Therefore, we propose to expand the analysis of mechanisms related to ArtinM effects on innate immune cells; and also to expand the investigation of the ArtinM effects on adaptive immune cells. Previous studies demonstrate that ArtinM acts on CD4+ T cells inducing a Th17 immune response, and also a Th1 profile, which contribute in therapy against fungal infection. However, several studies demonstrated that approach of antifungal drugs is limited and the modulation of immune response is important to eliminate systemic mycoses. Then, we propose to expand the application of ArtinM immunomodulatory activity on fungal infections, as follows: investigate the ArtinM effects associated with conventional antifungal drugs against experimental paracoccidioidomycosis; to develop strategies of cellular therapy on treatment of fungal infection through cellular activation triggered by ArtinM. Our proposal allows the development, in collaboration with chemical, of synthetic structures that mimic the immunomodulatory activity induced by carbohydrate recognition. (AU)