Immunomodulatory effects of Cryptococcus neoformans capsular polysaccharides on macrophage infected with Trypanosoma cruzi

Cryptococcus neoformans is an opportunistic fungal pathogen with a global distribution and is the causative agent of cryptococcosis, a disease that primarily affects immunocompromised individuals. The infection typically begins in the lungs and, in severe cases, can progress to meningoencephalitis and even death. Biochemical studies have shown that the fungal capsule is predominantly composed of glucuronoxylomannan (GXM), which accounts for approximately 88% of the total composition, followed by glucuronoxylomannogalactan (GXMGal, ∼10%) and mannoproteins (∼2%). Purified capsular components have been reported to exhibit distinct immunomodulatory effects: while GXM predominantly exerts immunosuppressive activity, inhibiting immune responses, GXMGal has been associated with immunoprotective properties. To evaluate these differential immunomodulatory effects in another infection model, we employed an in vitro system using murine macrophages infected with the Trypanosoma cruzi DM28c strain, followed by treatment with either GXM or GXMGal. Our results demonstrated that at 7 and 10 days post-infection, the number of trypomastigotes released was higher in GXM-treated conditions compared to GXMGal-treated conditions, even when macrophages were stimulated with interferon-γ. Additionally, amastigote counts were higher in macrophages treated with GXM, whereas GXMGal-treated conditions showed increased nitric oxide production. Cytokine quantification by ELISA revealed elevated TGF-β levels in GXM-treated cells and increased TNF-α levels in GXMGal-treated conditions. Furthermore, inhibition assays confirmed that these effects were reversed upon treatment with specific inhibitors. The preliminary in vitro infection and treatment model indicates that the immunomodulatory effects of C. neoformans capsular components persist even in a distinct infection setting. These findings reinforce the role of GXM as an immunosuppressive factor and GXMGal as an immunoprotective agent, suggesting that capsular components may differentially modulate host immune responses in various infectious contexts.