Cryptococcus neoformans Infection Induces IL-17 Production by Promoting STAT3 Phosphorylation in CD4+ T Cells

Abstract

Cryptococcus neoformans infection in the central nervous system is a severe infectious disease with poor outcomes and high mortality. It has been estimated that there are 220,000 new cases each year. Over 90% of C. neoformans meningitis cases were diagnosed in AIDS patients with CD4+ T cell count <100 cells/μl; however, the mechanism of cryptococcal meningitis in patients with normal immune functions remains unclear. IL-17 is a pro-inflammatory cytokine and plays an important role in anti-fungal immunity. Here we report that significantly high levels of IL-17 were predominantly detected in the cerebrospinal fluid of patients with either AIDS- or non-AIDS-associated C. neoformans meningitis but not in patients with tuberculous meningitis or non-neurosyphilis. Antifungal therapy minimized the IL-17 level in the cerebrospinal fluid. An in vitro mechanistic study showed that C. neoformans stimulation of healthy peripheral blood mononuclear cells prompted IL-17 production, and CD4+ T cells were the predominant IL-17-producing cells. IL-17 production by C. neoformans stimulation was STAT3 signaling dependent. Inhibition of STAT3 phosphorylation attenuated the C. neoformans-mediated IL-17 expression. Our data highlighted the significance of CD4+ T cells in antifungal immunity and suggested IL-17 as a diagnostic biomarker of C. neoformans infection and STAT3 as a checkpoint for antifungal targeted therapies.

Cryptococcus neoformans trehalose-6-phosphate synthase (tps1) promotes organ-specific virulence and fungal protection against multiple lines of host defenses

“…Neither have we found any contribution of CD4+ T cells to fungal control at later time-points in our disseminated model, where lungs were able to prevent tps1Δ fungal invasion in the T-cell-depleted mice at 2 and 3 weeks postinfection ( Figure 3B ). It is well established that Cryptococcus in the brain requires the adaptive, CD4+ T-cell-mediated immunity for anti-cryptococcal defenses ( Uicker et al., 2006 ; Neal et al., 2017 , Guo et al., 2022 ). Still brain invasion of tps1Δ C. neoformans in our disseminated model was significantly delayed (2- and 3-week postinfection time points).…”