"We believe this is a groundbreaking finding, although we're not yet sure how deep the ground is," says Jonathan Yewdell, M.D., Ph.D., a viral immunologist who led a team of scientists at the National Institute of Allergy and Infectious Diseases (NIAID). "This might be the 'grand canyon' of the flu, in terms of understanding this virus's virulence, or perhaps only a narrow side ravine."
The scientists turned up this new protein by accident, while sifting through bits and pieces of "junk" peptides. Junk peptides are short protein molecules the virus creates once it infects a cell and begins replicating. They form when the process that translates viral genes into proteins goes awry, Dr. Yewdell explains. In other words, junk peptides result from genetic mistakes.
"We weren't looking for new proteins at all. We assumed the 10 known influenza proteins were all there were," Dr. Yewdell says. "We just wanted to know if immune system cells had learned to recognize any of these junk peptides. We thought that was an interesting question."
The immune system cells of mice, in fact, did recognize one of the peptides. When the scientists examined the gene encoding this peptide more closely, they noticed it was "suspiciously long" for mere junk. Wondering if this molecule might be a bona fide protein, Dr. Yewdell's team decided to see how much of it was created in cells infected with the flu virus. If it were junk, there should be only a few random copies of the peptide here and there. If it were a protein, large quantities of the molecule should be present. Dr. Yewdell used a technique called immunofluorescence, which makes the molecule glow green, to show how much of it infected cells contained.
"The cells we looked at just lit up," Dr. Yewdell says. "We saw large amounts of this molecule in the mitochondria of flu infected cells, and we knew it was a real protein. It was one of those 'eureka' moments of discovery you live for in science. The junk turned out to be a jewel."
It turns out that this protein is created when ribosomes, the cellular machines that translate genes into proteins, begin reading the influenza gene called PB-1 in what was previously believed to be the wrong location. "One could say that lurking within the PB-1 gene is an overlapping gene that codes for this protein," explains Dr. Yewdell. "This alternate translation may have started out as a mistake, but the protein it produced was useful, so through evolution the gene was maintained and improved."
Tests showed the protein is toxic to human cells, especially immune system cells. "Next, we plan to learn more about the functions of this protein and how it accomplishes its tasks," Dr. Yewdell says. The team also wants to know whether this protein might have contributed to the virulence of the flu viruses that caused the Asian flu of 1957, the Hong Kong flu of 1968, and especially the Spanish flu of 1918, which killed 20 million people worldwide.
"Like many scientific discoveries, this one happened serendipitously, and it confirms the importance of supporting basic research on infectious diseases," concludes Anthony S. Fauci, M.D., NIAID director. "When you have good researchers exploring interesting questions, they are bound to turn up crucial information."
W Chen et al. A novel influenza A virus mitochondrial protein that induces cell death. Nature Medicine 17(12):1306-12 (2001).
Source: National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH)
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