TNF-α signaling is required for fungal clearance during brain infection with Cryptococcus neoformans via promoting the recruitment of CD4+ T cells and inflammatory monocytes

Abstract

Abstract Cryptococcus neoformans is a pathogenic fungus accounting for 180,000 deaths worldwide per year. The infection starts in the lung; however, the fungus can migrate to the brain, causing fatal meningoencephalitis primarily in immunocompromised individuals. TNF-α has been shown to mediate protective immunity in the lung during pulmonary infection with C. neoformans. However, the functions of TNF-α signaling during brain infection with C. neoformans remain poorly understood. Recent studies have shown that CD4+ T cells and inflammatory monocytes (IMs) mediate cryptococcal clearance in the brain at the cost of inducing immunopathology. Here, we study the role of TNF-α in the context of CD4+ T cells and IMs during brain infection with C. neoformans. We found that TNF-α levels in the brain were significantly increased during infection. The increase of TNF-α was associated with enhanced mRNA expression of various chemokines and accumulation of CD4+ T cells and IMs. Genetic ablation of TNF-α receptor (TNF-αR) in mice led to significantly higher brain fungal burdens and early mortality during C. neoformans infection. Infected TNF-αR−/− mice displayed significantly reduced recruitment of CD4+ T cells and IMs in the brain compared to infected wild-type mice. This was accompanied with reduced mRNA levels of KC, MIP-2, CCL2 and CCL7. Interestingly, deficiency of TNF-αR also resulted in a significant drop in the mRNA levels of ICAM-1 and VCAM-1 as well as the expression of CD11a and VLA4 in CD4+ T cells and IMs. Collectively, these results suggest TNF-α signaling is essential for the recruitment of CD4+ T cells and IMs, mediating fungal clearance during brain infection with C. neoformans. Supported by AI131219 and AI131905