Yale scientists identify an early line of defense against West Nile virus

In the five years since the West Nile virus made its first appearance in New York, it has spread to virtually all of the contiguous 48 states. There has been an alarming increase in infections and the most serious cases have resulted in death from encephalitis. The Centers for Disease Control and Prevention reported about 9,000 cases of West Nile infection last year—more than double the number reported in 2002—and more than 200 deaths. Among those looking for ways to prevent and treat West Nile is Erol Fikrig, M.D., professor of medicine (rheumatology), who has spent the past 11 years investigating the biology of arthropod-borne illnesses, including Lyme disease.

Most of those infected with West Nile virus experience only mild illness, and some have no symptoms at all. Only about 30 percent of patients, many of them elderly or with compromised immune systems, succumb to the most serious form of the illness characterized by encephalitis. In a paper published last September in The Journal of Immunology, Fikrig and his colleagues offered a new explanation for why most patients are able to successfully fight off the virus shortly after infection.

In 2001, Fikrig’s group successfully immunized mice against West Nile by injecting the mice with genetically engineered fragments of the protein shell that encapsulates the virus; exposure to the harmless fragments caused the mice to develop antibodies against the virus. But it took three to four days for the vaccinated mice to deploy these antibodies, and clinical experience has shown that time is of the essence in treating West Nile.

Fikrig thought that in mildly ill patients West Nile’s relentless pace might have been stalled by some early immune response that clears the virus and gives these individuals time to marshal an antibody defense. He concluded that understanding these very early immune reactions is crucial to preventing severe illness and death. Talking one day with Joseph E. Craft, M.D., HS ’77, professor of medicine and immunobiology and chief of the Section of Rheumatology, Fikrig learned of an immune cell with all the right characteristics.

Craft, who specializes in autoimmune illnesses such as lupus, has extensively studied gamma delta T cells, which are believed to serve as a bridge between innate immunity, the body’s first line of defense, and later immune reactions. “We thought that gamma delta T cells might play a role in this early time window,” Craft said.

Along with postdoctoral researcher Tian Wang, Ph.D., Fikrig tested the hypothesis. Wang injected West Nile into a strain of mice that lack gamma delta T cells and found that these mutant mice were markedly more susceptible to infection than normal animals, and quicker to develop encephalitis and die once infected. When Wang injected activated gamma delta T cells into the mutants, they fought off the disease.

But Fikrig isn’t yet sure just how gamma delta T cells mount an early defense against West Nile. With the help of Eileen P. Scully, an M.D./Ph.D. student in Craft’s lab, Fikrig showed that the cells multiply dramatically and are activated quickly after infection. Scully also demonstrated a link between early and late immune reactions; gamma delta T cells produce interferon gamma, a potent molecule that attacks viruses and stimulates the immune system to produce antibodies.

Next Fikrig plans to see whether gamma delta T cells work in the same way in humans. If the results hold up, pharmaceutical companies might be able to make antiviral drugs that fight West Nile by boosting gamma delta T cell activity or interferon gamma production.