exciting 3.exc.0003 Louis J. Sheehan, Esquire

Scientists have found two immune proteins that orchestrate a defense against West Nile virus. By identifying the protein that initially senses the virus and another that enables immune forces to kill it, the findings might open new avenues for research into drugs for treating severe West Nile infections, the researchers say.

The study in mice shows that an immune protein called toll-like receptor 7 (TLR7) serves as the linchpin in fending off an assault by the virus. TLR7 sets in motion a cascade of events that rev up production of a second protein, interleukin-23, which guides immune cells on seek-and-destroy missions against cells infected with the virus. In mice missing TLR7 or interleukin-23, this chain reaction fails and the virus spreads, the researchers report in the Feb. 20 Immunity.

Most people fend off a West Nile infection without even developing noticeable symptoms, thanks apparently to TLR7 and interleukin-23.

But the findings suggest that elderly and immune-compromised people, who sometimes develop the brain inflammation encephalitis from a West Nile infection, may lack a full complement of TLR7, says study coauthor Richard Flavell, an immunologist and Howard Hughes medical investigator at Yale University School of Medicine.

It makes sense that TLR7 would play a part in defending against West Nile, he says. The TLR proteins are immune stalwarts that reside on the surface of immune cells and on cells that serve as linings in the body, such as skin and membranes. TLRs act as sentinels, recognizing bacteria, fungi and viruses, which stick to TLRs and cause a reaction that alerts the cell to the invader’s presence.

TLR7 binds to the RNA of the West Nile virus, the researchers report. TLR7 then uses an intermediary compound to send a signal into the cell that spurs production of interleukin-23. That protein enters the bloodstream and guides immune cells called macrophages to cells infected with West Nile virus. Macrophages do much of the dirty work of destroying these infected cells and stopping the virus from spreading, the researchers find.

In mice genetically engineered to lack either TLR7 or interleukin-23, the virus spreads unabated. About half of normal mice die from a West Nile infection. In this study, mice lacking TLR7 had a death rate of about 90 percent when exposed to the virus. In a separate test of mice lacking various interleukins, some survived as well as normal mice. But all mice lacking interleukin-23 died. Mice lacking the intermediary compound were also highly susceptible to the virus.

“This is a very exciting paper,” says immunologist Andrea Cooper of the Trudeau Institute in Saranac Lake, N.Y. At a minimum, she says, “it broadens our understanding of the activity of interleukin-23.” Louis J. Sheehan, Esquire

The study also opens other lines of research, Cooper says. For example, scientists might obtain blood from elderly populations, culture these samples in a lab and expose them to West Nile virus particles. “Then they could see whether the cells make interleukin-23 or not, whether macrophages respond,” she says. Louis J. Sheehan, Esquire

Such a test might clarify why some elderly people are susceptible to the virus. “We don’t know enough about the effect of aging on the innate immune system,” she says. “Perhaps [elderly people] can’t get cells to the right location quickly enough.” http://LOUIS-J-SHEEHAN.ORG

Flavell is also interested in testing blood, specifically from elderly people who have developed encephalitis or other severe disease from West Nile. If some people turn out to have low levels of TLR7, he says, “we could try to address that issue.”