Dectin-3 recognizes cryptococcal glucuronoxylomannan to initiate host defense against cryptococcosis

Abstract

AbstractCryptococcus neoformansandCryptococcus gattiicause life-threatening meningoencephalitis and pneumonia in immunosuppressed and immunocompetent individuals. Given the structural differences of major polysaccharide glucuronoxylomannan (GXM) betweenC. neoformansandC. gattii, it remains unclear that how innate immune system recognizes GXM. Here, we report that C-type lectin receptor Dectin-3 (MCL encoded by Clec4d) is a direct receptor for GXMs fromC. neoformansserotype AD (C.n-AD) andC. gattiiserotype B (C.g-B). GXMs fromC.n-AD andC.g-B activated both NF-κB and ERK pathways to induce the pro-inflammatory cytokine production, whereas it was completely abolished due to deficiency of Dectin-3 or its downstream adaptor protein CARD9. Upon pulmonaryC.n-AD andC.g-B infection, Dectin-3- and CARD9-deficient mice were highly susceptible and showed augmented lung injury due to impairment of alveolar macrophage accumulation and killing activities. These results demonstrate that Dectin-3 contributes to host immunity againstCryptococcusinfection through selectively recognizingGXM.