ITHACA, N.Y. -- Two Cornell University researchers have found a pathway that is critical for the flu virus to enter and infect a cell. The discovery could lead to the development of antiviral medications and vaccines that would target all influenza viruses.

The newly discovered pathway occurs after the virus attaches to a cell. The next stage of infection, the Cornell researchers say, involves an unknown co-receptor that allows the virus to infect the cell.

"Now that we know there's a second step involved in influenza infection -- that a co-receptor is crucial for the virus to enter a cell -- we can go after it," says Gary R. Whittaker, assistant professor of virology at the College of Veterinary Medicine at Cornell.

"Once we identify the receptor, we expect that a whole new avenue of antiviral medications and vaccines could be developed that would target all influenza viruses, not just one strain at a time," he says.

Whittaker and Victor C. Chu, a graduate student in comparative biomedical sciences, have published their findings in the Proceedings of the National Academy of Sciences (Dec. 28, 2004; Vol. 101, 52, 10153-18158). It is an open-access article, freely available online at http://www.pnas.org/cgi/reprint/101/52/18153 .

Scientists have known for about 50 years how the influenza virus attaches to cells before it infects them. Previous work focused on red blood cells, which are suitable experimental systems for examining virus attachment. However, red blood cells don't have nuclei and can't be infected by the virus. Until now, scientists had never found a mammalian cell -- with a nucleus -- that resists the influenza virus. The Cornell researchers, however, have identified a line of nucleated cells that are resistant to infection by the flu virus. The critical factor that protects these cells from infection is the lack of a specific surface receptor comprising N-linked glycoprotein.

Thus, although the influenza virus can still attach to these cells, without the surface N-linked glycoprotein, the virus cannot infect them. Whittaker points out that the latest influenza discovery is paralleling the research advances with the HIV-AIDS virus about nine years ago, when a second HIV co-receptor was discovered. This enabled researchers to develop new drugs that are now in clinical trials.

Influenza kills some 20,000 people every year in the United States and up to one-half million people worldwide. New strains keep cropping up for which vaccines must be developed. The development of vaccines for each strain is costly, time-consuming and not always effective; sometimes new and more virulent strains crop up by the time a new vaccine for a less virulent strain is available. Whittaker also notes the concern about a bird flu virus in Southeast Asia that could overwhelm our ability to control it. Potentially this avian virus threatens the lives of tens of millions of people worldwide.

Whittaker explains that the influenza virus first binds to the host cell via a sialic acid receptor -- a surface-cell carbohydrate that is near universal -- and then fuses with it.

"These events generally have been well characterized from a biochemical and biophysical perspective, but many of the cell biological aspects of virus entry have been unclear," Whittaker says. Instead of red blood cells, Whittaker and Chu turned to a line of Chinese hamster ovary (CHO) cells, which have been used since the 1970s to study cell genetics. The normal line of CHO cells get infected -- just as all nucleated cells do -- but a mutant line of these cells, called Lec1 cells, are deficient in the surface N-linked glycoprotein and are resistant to the influenza virus.

"Our work shows that the influenza virus requires a protein to enter cells and that sialic acid, although an efficient attachment factor, is not sufficient for infection," says Whittaker. He notes that Lec1 cells may also provide a new model for influenza virus infection research.

The research was supported, in part, by a Career Investigator Grant from the American Lung Association and by a National Institutes of Health grant.