Collateral Damage during Dengue Virus Infection: Making Sense of DNA by cGAS

Abstract

Early sensing of viral components or infection-induced tissue damage is a prerequisite for the successful control of pathogenic viruses by the host innate immune system. Recent results from our laboratory show how immune cells use the DNA-sensing machinery to detect intracellular damage generated early during infection by an RNA virus, namely, dengue virus (DENV). Conversely, we found that DENV can efficiently dismantle this sensing mechanism by targeting the cyclic GMP-AMP synthase (cGAS) and the stimulator of interferon (IFN) genes (STING), two crucial host factors involved in DNA detection and type I IFN production. These findings highlight the relevance of the DNA-sensing mechanism in the detection and control of infections by RNA viruses. In this review, we discuss how DENV modulates the innate immune DNA-sensing pathway, activated in the context of cellular damage during infection.

Keywords: DNA sensing; STING; cGAS; damage; dengue virus; innate immunity; interferon; mitochondria; mtDNA.

FIG 1

Sensing of DENV infection by host cells. DENV replicates in ER membrane-derived vesicles, where it hides its replication products from the cytosolic RIG-I-like receptors (RIG-I and MDA-5), which can recognize viral RNA and signal type I IFN production through MAVS and STING. The DENV NS2B3 protease complex cleaves STING in the ER membrane to inhibit viral-RNA and self-DNA detection. Some viral proteins reach the mitochondrial membrane, resulting in mitochondrial stress and subsequent mtDNA leakage. The DNA sensor cGAS can detect mtDNA in the cytoplasm to engage the type I IFN production through the synthesis of cGAMPs, which can activate STING in the infected cell or translocate to neighboring cells via gap junctions. DENV NS2B, NS3, and NS2B3 proteins can interact with cGAS and inhibit its function. DENV NS2B interacts with cGAS and induces its degradation by an autophagy–lysosome-dependent mechanism, resulting in an inability to produce type I IFN by the host. CM, convoluted membrane; VP, vesicle packets. (Courtesy of Mount Sinai Health System, reproduced with permission.)