The detecting of pathogen-derived DNA by cytoplasmic-pattern pathogen recognition receptors (PRRs) is essential for establishing the host immunity in microbial infection. Stimulator interferon of genes (STING), a membrane-associated protein that is localized at endoplasmic reticulum, recognizes cyclic GMP-AMP (cGAMP) derived from viral DNA, and induces production of type-I IFNs and inflammatory cytokines, which are essential to suppress viral replication. Therefore, STING is recognized as an important mediator for the control of viral infection. However, it is unclear whether STING is required for the anti-fungal immunity.
Cryptococcus neoformans is a cytozoic fungus which causes severe diseases such as meningitis and pneumonia. Unlike other fungi, C. neoformans has a capsule that functions to escape from innate immune response. It was known that PRRs are important roles for the control of C. neoformans dissemination. Toll-like receptors and the C-type lectin receptor mannose receptor sense pathogen-associated molecular patterns (PAMPs) from C. neoformans. Upon ligand binding, they induce Th-1-associated cytokines and type-I IFNs, driving adaptive immune responses.
Because Th1-associated cytokines/IFNs are produced by signaling downstream of STING, we examined the role of STING in C. neoformans infection. In vitro, STING-/- bone marrow-derived dendritic cells (BMDCs) produced higher amounts of IL-6 and IL-10, but not IL-12p70, than WT BMDCs following stimulation with C. neoformans Cap 67, an acapsular strain, whereas both WT and STING-/- BMDCs did not produce cytokines following stimulation with C. neoformans YC-13, a capsular strain. When stimulated with C. neoformans-derived DNA, both WT and STING-/- BMDCs did not secret type-I IFNs and inflammatory cytokines. In vivo, STING-deficient mice showed enhanced resistance to C. neoformans YC-13 infection. These results suggest STING dampens innate immune response in C. neoformans infection by sensing pathogenic components with unknown mechanisms.