DECTIN-1 stalk length determines binding ability, immune response, and survival in a mouse model of coccidioidomycosis.

Coccidioidomycosis is a leading cause of pneumonia in the endemic area of the Sonora desert and the central valley of California. The causative agent are the fungi Coccidioides immitis and C. posadasii. While most infections ultimately resolve without treatment, some infections spread to the periphery and cause serious and even fatal illness. Much work has shown that a T cell response with production of interleukin-17A and interferon ɣ is critical. Less work has focused on innate responses that ultimately set the stage for the adaptive response. Genetic analysis in both mice and man have shown an important role for DECTIN-1. DECTIN-1 is a C-type lectin receptor that recognizes β-glucans, the main cell wall component of many fungi. Initial recognition through DECTIN-1 modulates fungal binding, host cell uptake, and induces production of a number of cytokines and chemokines. C57BL/6 mice carry a point mutation altering splicing of exon 3, leading to a shorter DECTIN-1 protein lacking a portion of the extracellular stalk. We created mutant C57BL/6 mice to allowing expression of a long-stalk DECTIN-1 consistent with other mouse strains and humans. We directly examined the role of DECTIN-1 stalk length on resistance to infection with the β-glucan-dominant pathogen, C. posadasii. C57BL/6 mice expressing long-stalk DECTIN-1 bound more β-glucan per cell, produced more cytokines, and decreased mortality and dissemination after Coccidioides infection compared with wild-type littermates. The length of the DECTIN-1 stalk controls the outcome of Coccidiodes infection by differential binding and early production of protective cytokines.