For the immune system to do its job in fighting off disease, it first has to be able to detect foreign intruders. Scientists have known for some time that when bacteria, viruses and other pathogens set off alarms in the immune system, this leads to the production of molecules such as interferon that rev up the body’s defenses. But until now, researchers lacked evidence from animal experiments to back up the theory of how the DNA from these pathogens first triggers this immune-activating cascade in the immediate, ‘innate’ immune response.
Previously, immunologist Zhijian “James” Chen, of the University of Texas Southwestern Medical Center in Dallas, and his colleagues showed that when bacteria or viruses wile their way into host cells—either by tricking cell receptors to allow entry or getting engulfed by the cell membrane—their foreign DNA activates an enzyme called cyclicguanosine monophosphate–adenosine monophosphate synthase (cGAS). This enzyme then binds to the intruder’s DNA and triggers the next step in the cascade of immune events: the production of a second messenger, a small molecule called cyclicguanosine monophosphate–adenosine monophosphate (cGAMP).
In a mouse study published online today, Chen’s team demonstrates evidence of cGAS activity, in vivo, against infectious agents such as herpes virus, which uses DNA as its genetic material (unlike influenza or rotaviruses, which are examples of RNA-based pathogens).
The researchers exposed five mice that they had genetically engineered to lack cGAS to herpes simplex virus 1 (HSV1). All of those mice died from viral encephalitis, as did five control mice that also were exposed to the virus. Crucially, though, several of the mice engineered to lack cGAS died three days after exposure and had high titers of HSV1 in their brain tissue, whereas their control counterparts died beginning on the sixth day and had no detectable HSV1 in the brain. The cGAS-deficient rodents also had markedly lower levels of interferon—a key signaling molecule in of the immune system—indicating that mice without cGAS couldn’t mobilize an effective immune defense.
The role of cGAS show in the earlier in vitro study and this new rodent experiment has impressed other scientists. “This is a brand new antiviral mechanism that we didn’t know before,” says Luke O’Neill, a biochemist at Trinity College in Dublin, Ireland. “This research has really galvanized the field.”
To show that cGAS wasn’t specific to one type of cell, Chen’s team infected a variety of mouse cells—lung cell fibroblasts, dendritic cells and macrophages—with DNA from multiple sources. Those cells engineered to lack cGAS failed to produce interferon, for the most part. According to Chen, having an enzyme that detects foreign DNA regardless of which cell is invaded, or where the genetic material came from is “pretty clever” of the immune system: “DNA should stay in the cell nucleus or the mitochondria. When it shows up anywhere else in the cell it’s a clear sign that something is wrong.”
Chen adds that knowing how the immune system reacts to foreign DNA may help researchers figure out how to develop therapeutics for autoimmune diseases, such as lupus, in which scientists believe ‘self’ DNA might mistakenly leak out of the cell nucleus and mobilize the defense system to attack its own body.
The scientists also explored a potential therapeutic role for cGAMP as a powerful booster to the immune system. They found that mice that received injections of a protein derived from eggs called ovalbumin (OVA) in combination with cGAMP produced more protective antibodies against OVA than those that received the injection without cGAMP. With these immune boosting effects, Chen says that cGAMP might one day be used to improve the efficacy of human vaccines, and perhaps used in the development of effective immunizations against HIV and malaria.
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