Scientists supported by the National Institute of Allergy and Infectious Diseases (NIAID) have discovered why some influenza viruses are uncommonly deadly.
In a paper published in the Aug. 18 issue of the Proceedings of the National Academy of Sciences USA, they describe an unusual molecular mechanism that amplifies the disease-causing power of influenza A virus. This mechanism could be a new marker for scientists to examine when attempting to predict the potential for a newly emergent influenza A virus to cause a pandemic. Though still to be proved, their discovery may explain the longtime mystery of how the virus that caused the 1918 influenza pandemic caused more than 20 million deaths worldwide.
"Their findings point us in a direction to better understand the pathology of these more virulent influenza viruses," notes Dominick Iacuzio, Ph.D., program officer for influenza and related viral respiratory diseases at NIAID.
Influenza A viruses possess two surface proteins, hemagglutinin (HA) and neuraminidase (NA). To become infectious, the HA molecule must first be cut into two subunits that help the virus attach to human cells. Normally, influenza viruses remain confined to the respiratory tract because the protease enzymes that cleave HA are common in the lungs and trachea but not in other tissues.
Yoshihiro Kawaoka, D.V.M., Ph.D., and Hideo Goto, D.V.M., Ph.D., of the University of Wisconsin School of Veterinary Medicine in Madison, have discovered that this human influenza A virus is more virulent because it employs a more ubiquitous enzyme, plasmin, to help chop HA in two.
The scientists studied a virus descended from the strain that caused the 1918 pandemic and adapted to grow in mice. Through their experiments, they found that its NA molecule has two distinct structural features that enable it to bind and trap plasminogen, a precursor to plasmin, and thereby accelerate HA cleavage and promote widespread infection of cells.
The investigators tested 10 other human, swine and avian viruses, and found no evidence of the same mechanism at work, indicating that the ability to sequester plasminogen and thereby enhance HA cleavage was a unique property of this particularly virulent strain of human influenza A virus.
"This is a mechanism that we never knew existed in influenza viruses," says Dr. Kawaoka. "Now we have additional markers that we can look for when a peculiar outbreak of human or animal flu occurs," he adds. These two structural features of the NA molecule "should be considered when evaluating the health hazard posed by human influenza viruses," they write in their article. Any strain with an NA molecule possessing these two features, they add, "should be regarded as potentially dangerous."
Scientists have known for years that certain bacteria, such as group A streptococci, contain plasminogen-binding proteins that make it easier for these bacteria to infect tissues. But this is the first example, Dr. Kawaoka notes, of a virus that contains a plasminogen-binding protein. It is highly likely, he says, that such proteins will be found in other pathogenic viruses as well.
NIAID is a component of the National Institutes of Health (NIH). NIAID conducts and supports research to prevent, diagnose and treat illnesses such as HIV disease and other sexually transmitted diseases, tuberculosis, malaria, asthma and allergies. NIH is an agency of the U.S. Department of Health and Human Services.
H Goto and Y Kawaoka. A novel mechanism for the acquisition of virulence by a human influenza A virus. Proceedings of the National Academy of Sciences USA 95:10224-28 (1998).
JK Taubenberger. Influenza virus hemagglutinin cleavage into HA1 and HA2: no laughing matter. Proceedings of the National Academy of Sciences USA 95:9713-15.
Note: Copies of the paper and the commentary can be requested directly from PNAS by calling (202) 334-2138.
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