Human Genes Associated With West Nile Virus Infection

Since West Nile virus (WNV) first appeared in the United States a decade ago, it’s become a seasonal epidemic, flaring up in the summer and continuing into the fall. Unfortunately, our understanding of the virus on a molecular level has been limited. A new study has now identified over 300 human proteins involved in WNV infection, exposing numerous potential antiviral targets.

In 2007, WNV caused over 3,600 reported infections nationwide, leading to 124 deaths, according to the Centers for Disease Control and Prevention. Human cases have been reported throughout the continental United States and in Canada and Mexico.

WNV belongs to a group of disease-causing viruses known as flaviviruses that are usually spread by ticks or mosquitoes. The virus encodes only 10 proteins of its own, suggesting that it needs many human cellular proteins for infection. Supported primarily by NIH’s National Institute of Allergy and Infectious Diseases (NIAID), a research team—led by scientists at the Yale University School of Medicine, Massachusetts General Hospital and the Howard Hughes Medical Institute—set out to make a comprehensive molecular portrait of WNV–human cell interactions.

The researchers used a technique called RNA interference to “silence” genes and see which ones affected WNV infection. They silenced over 21,000 different genes in human cells in the laboratory and infected the gene-silenced cells with WNV. They then looked for viral envelope protein in the cells to identify genes whose absence either helps or hinders infection.

As they reported in the advanced online edition of Nature on August 7, 2008, the researchers found 283 genes that help WNV infect cells and 22 involved in resisting infection. An analysis of the genes revealed a complex dependence of the virus on the human cells it infects, involving a wide variety of molecules and cellular pathways.

The researchers tested the genes they found against dengue virus, a related flavivirus, to see if they shared common molecular pathways for infection. About 36% of the genes that WNV uses for infection also reduced dengue virus infection when silenced. All the 22 genes involved in resisting WNV infections also allowed dengue virus to infect cells more easily when they were silenced.

This study revealed numerous potential antiviral targets against WNV. It also forms a model for understanding infection by other flaviviruses, which include tick-borne encephalitis, Japanese encephalitis and yellow fever in addition to dengue viruses.

—by Harrison Wein, Ph.D.