Researchers at the Icahn School of Medicine at Mount Sinai recently used the dengue virus as a model to identify the signaling pathway used to initiate an immune response in the body and how the virus counteracts that mechanism to evade immune detection.
“Previous studies have shown that human viruses have acquired specific mechanisms to strategically avoid detection by the innate immune system,” Ana Fernandez-Sesma, author of the study and professor of microbiology at the Icahn School, said. “Active strategies are used by viruses to minimize the ability of cells to detect and respond to infection, allowing sufficient time for the production of viral progeny.”
Fernandez-Sesma said the study showed how dengue fever employs multiple techniques to avoid detection, what mechanisms cells use to recognize traces of viral infection within a cell, and the methods viruses have acquired to obstruct them.
The study identified cyclic GMP-AMP synthase (cGAS) as the protein that initially detects viral infection. It first recognizes that DNA has escaped the mitochondria of a cell and entered the cytoplasm, which the authors describe as an unusual event. When a host is infected with dengue, cGAS recognizes traces of mitochondrial DNA released into the cytoplasm, which happens in the beginning stages of infection.
Then, once cGAS binds to DNA, the protein activates a series of cascading chemical triggers known as the cGAS/cGAMP/STING sensing pathway, which begins type I interferon signaling and starts the immune response.
The authors said that dengue reduces the likelihood of triggering the cGAS/cGAMP/STING pathway by degrading cGAS and preventing it from binding with mitochondrial DNA in the cytoplasm of the cell.
“Until now, it has not been understood how cGAS can play such a critical role in identifying these RNA viruses,” Fernandez-Sesma said. “Our data strongly suggest that mitochondrial damage and the release of mitochondrial DNA are intrinsic collateral damage during [dengue] infection and prompt cGAS to activate the necessary immune signaling pathways.”
The study was published in a recent issue of the journal Nature Microbiology.