GLYCOLIPID SENSING AND INNATE IMMUNITY TO PARACOCCIDIOIDOMYCOSIS

Abstract

Paracoccidioidomycosis (PCM) is the most important systemic mycosis in Latin America. As in other endemic infectious diseases, only a minority of the exposed individuals will develop the disease; however, the mechanisms involved in susceptibility/resistance to PCM remain unknown. To address this we investigated some aspects of the innate immunity of 15 healthy individuals who have had PCM in the past and had been cured without sequels >10 years previously, representing the “susceptible” group, and 20 healthy individuals without PCM in the past (controls). For this we also used two glycolipids present in the fungus membrane, monohexosylceramide and glycosylinositol-phosphorylceramide, previously shown to exhibit immunological properties. There were significant lower expression of the costimulatory molecules CD86 and HLA-DR by susceptible individuals' monocytes and dendritic cells. Other costimulatory molecules such as CD80/CD40, PAMP receptors (TLR-4/TLR2/dectin-1) and CD1d expression were not different between the two groups. Both glycolipids further decrease CD86 and HLA-DR expression, while increased dectin-1 expression in both cell subsets. Monocytes and DCs' from susceptible individuals presented higher constitutive IL-10 production than control individuals, while TNF and IL-12 productions were comparable. DC ́s ability to induce lymphocyte proliferation to a fungal antigen was in general higher in controls than susceptible individuals; this DC function was suppressed by both glycolipids. Both glycolipids also blocked DC's ability to induce lymphocyte proliferation to P. brasiliensis immunodominant antigen. Subtle but significant differences in innate immunity functions and responses to P. brasiliensis glycolipids between “susceptible” and control individuals may underlie the mechanisms involved in resistance/susceptibility to paracoccidioidomycosis.