Dengue viruses cleave STING in humans but not in nonhuman primates, their presumed natural reservoir
Alex C Stabell,
Nicholas R Meyerson,
Rebekah C Gullberg,
Alison R Gilchrist,
Kristofor J Webb,
William M Old,
Rushika Perera,
Sara L Sawyer
Affiliations
Alex C Stabell
Department of Molecular, Cellular and Developmental Biology, University of Colorado Boulder, Boulder, United States
Nicholas R Meyerson
Department of Molecular, Cellular and Developmental Biology, University of Colorado Boulder, Boulder, United States
Rebekah C Gullberg
Arthropod-borne and Infectious Diseases Laboratory, Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, United States
Alison R Gilchrist
Department of Molecular, Cellular and Developmental Biology, University of Colorado Boulder, Boulder, United States
Kristofor J Webb
Department of Molecular, Cellular and Developmental Biology, University of Colorado Boulder, Boulder, United States
William M Old
Department of Molecular, Cellular and Developmental Biology, University of Colorado Boulder, Boulder, United States
Rushika Perera
Arthropod-borne and Infectious Diseases Laboratory, Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, United States
Human dengue viruses emerged from primate reservoirs, yet paradoxically dengue does not reach high titers in primate models. This presents a unique opportunity to examine the genetics of spillover versus reservoir hosts. The dengue virus 2 (DENV2) - encoded protease cleaves human STING, reducing type I interferon production and boosting viral titers in humans. We find that both human and sylvatic (reservoir) dengue viruses universally cleave human STING, but not the STING of primates implicated as reservoir species. The special ability of dengue to cleave STING is thus specific to humans and a few closely related ape species. Conversion of residues 78/79 to the human-encoded ‘RG’ renders all primate (and mouse) STINGs sensitive to viral cleavage. Dengue viruses may have evolved to increase viral titers in the dense and vast human population, while maintaining decreased titers and pathogenicity in the more rare animals that serve as their sustaining reservoir in nature.
