Cells catch fusing viruses by spilling their own DNA, Harvard team finds

The alarm itself was not the mystery. Virologists have known for years that a cell hit by an enveloped virus such as herpes simplex sends out interferon within about an hour. A protein called cGAS, which senses stray DNA in the cell body, sets that off ^[16]. The open question was which DNA cGAS was reading. One idea held that some virus particles rupture after they enter the cell but before they reach the nucleus, spilling their own genetic material ^[17]. That could not be the whole story, because cGAS also fires against RNA viruses, which have no DNA ^[6].

The answer the team reached is that the DNA is the cell's own ^[5]. Nicolás Romero and colleagues worked in human cell cultures with a herpesvirus engineered so it could not replicate on its own, which rules out the DNA coming from viral copying inside the cell ^[7][11]. As the virus's envelope fuses with the outer membrane and the particle enters the cytoplasm, the actin microfilaments that hold the cell's shape go into turbulent contractions. Those tremors tear an opening in the nuclear membrane ^[3]. Host DNA fragments leak out. cGAS finds them, raises the alarm, and interferon follows to block the virus from taking hold ^[4].

To check that this was not a quirk of herpesvirus, the researchers repeated the experiment with other enveloped viruses, including parainfluenza, and saw the same DNA expulsion. They concluded that any virus entering by membrane fusion sets it off ^[9]. The control that pins the cause is the pair of non-enveloped viruses they also tested: those get in by endocytosis, and they produced neither the DNA leak nor the interferon response ^[10]. The team confirmed the picture with light microscopy, transmission electron microscopy and immunogold labeling ^[8].

"It's important to understand the details of how viruses and the body's immune system interact," said David Knipe, the study's senior author at Harvard Medical School, "because those details give us a better idea of how we can use the same techniques to build better medicines" ^[13]. The team suggests the work could feed into better vaccines and into oncolytic viruses engineered to infect and kill cancer cells ^[15]. The experiments ran in human cell cultures with a replication-deficient herpesvirus, so they identify the trigger without showing that tuning it improves any vaccine or therapy in an animal or a person ^[7].

Knipe has studied the contest between herpesvirus and the immune system at the cellular and molecular level for decades ^[12]. He framed the value of that kind of question this way: "Answering chains of puzzling questions without obvious, immediate utility enables us to engineer unexpected mechanisms we wouldn't have been able to conceive of otherwise" ^[14].