DNA-induced 2′3′-cGAMP enhances haplotype-specific human STING cleavage by dengue protease

Significance

Dengue virus (DENV) antagonizes the DNA sensing cGAS-STING pathway to subvert innate immunity, but how DENV protease-mediated human STING cleavage contributes to DENV pathogenesis remains obscure. Here, we found that STING haplotype frequency varies among different subhuman populations, and different haplotypes respond differently to DENV protease. The cleavage of a DENV protease-sensitive STING can be further enhanced by coculture with neighboring cells producing 2′3′-cGAMP, either by DNA transfection of cGAS or by reactivating Epstein–Barr virus from latent infection. Thus, DENV infection trims down human STING-mediated innate immunity in a haplotype-specific manner. The genetic background of host STING and bystander coinfection of pathogens triggering 2′3′-cGAMP production may be the missing link between STING cleavage and DENV pathogenesis.

Abstract

The cytosolic DNA sensor cGMP-AMP synthase (cGAS) synthesizes the noncanonical cyclic dinucleotide 2′3′-cGAMP to activate the adaptor protein stimulator of IFN genes (STING), thus awakening host immunity in response to DNA pathogen infection. However, dengue virus (DENV), an RNA virus without a DNA stage in its life cycle, also manipulates cGAS-STING–mediated innate immunity by proteolytic degradation of STING. Here, we found that the sensitivity of STING to DENV protease varied with different human STING haplotypes. Exogenous DNA further enhanced DENV protease’s ability to interact and cleave protease-sensitive STING. DNA-enhanced STING cleavage was reduced in cGAS-knockdown cells and triggered by the cGAS product 2′3′-cGAMP. The source of DNA may not be endogenous mitochondrial DNA but rather exogenous reactivated viral DNA. Cells producing 2′3′-cGAMP by overexpressing cGAS or with DNA virus reactivation enhanced STING cleavage in neighboring cells harboring DENV protease. DENV infection reduced host innate immunity in cells with the protease-sensitive STING haplotype, whose homozygote genotype frequency was found significantly reduced in Taiwanese people with dengue fever. Therefore, the human STING genetic background and DNA pathogen coinfection may be the missing links contributing to DENV pathogenesis.