Your cells are little chatterboxes that can’t keep a thing to themselves. They narrate their day-to-day activities for all to hear–every ache and pain or coming and going. With cells, everything is on the surface.
And it’s a good thing, too, because the immune system, like an overprotective parent, needs to hear exactly what’s going on to make sure we are safe. Cells’ preferred method of communication is to display molecular flags on their membranes. Such flags let the immune system know if a cell has been infected by a virus or has turned cancerous. But some viruses can gag cells so that the immune system has no idea what’s happening.
Hidde Ploegh, an MIT biology professor and member of the Whitehead Institute for Biomedical Research, wants to know how they do it. In his lab, researchers are zeroing in on the tactics that viruses and bacteria use to silence cells. “We think that by inspecting these viruses [and bacteria] closely, we can get a glimpse not only at their evasive functions but also at the workings of the healthy immune system,” says Ploegh.
The cells of the immune system include many kinds of killer, memory, and chatterbox cells connected through complex communication networks. The deadliest human diseases–including tuberculosis, HIV, and cancer–are very good at hiding their presence from the immune system. Exactly how they do this is not well understood: there are many places in the networks where a disease could disrupt or destroy a signal.
Ploegh is particularly interested in herpesviruses–a large, ancient family of viruses, of which eight infect humans–because many of them can stop the communication process before it starts by preventing chatty cells’ flags from going up. “This family has evolved a bag of tricks with which they frustrate this whole process,” he says.
What Ploegh finds especially fascinating about herpesviruses is that unlike most other disease-causing microbes, once they infect you, they never go away. “What these viruses have learned,” he says, “is not only how to infect the host and hide within it but also how to reactivate from their latent state,” causing fever, sores, and other symptoms sometimes years and years later. “The virus comes out of hiding in the face of an immune system that already knows about its presence, and it can still come out on top and be transmitted to the next host. That’s a pretty remarkable set of strategies.”
In particular, Ploegh has focused on a herpesvirus called human cytomegalovirus (HCMV), which is so prevalent that 50 to 80 percent of Americans harbor it by the age of 40. Infected people usually have no symptoms, but the virus can cause eye inflammation, liver failure, and death in people with compromised immune systems, such as AIDS patients.
Ploegh’s research has shown that HCMV is among the herpesviruses that can cloak themselves by preventing the cells they infect from displaying their molecular flags to the immune system. All human cells, whether infected or not, ordinarily display on their surfaces constantly rotating samples of the proteins being made inside. Immune-system cells known as killer T lymphocytes circulate through the blood and the lymphatic system to “read” these samples. If a cell is displaying a snippet of a protein not normally made by healthy cells–like a cancer protein or a viral protein–the killer T lymphocytes wandering by will detect it and kill the cell. “You might consider this the early-warning system by which the T lymphocyte knows what’s going on deep inside a cell,” says Ploegh. “If the virus could disarm that early-warning system, it would be temporarily invisible to killer T cells.”