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
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
"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.
Press releases, fact sheets and other NIAID-related materials are
available via the NIAID Web site at http://www.niaid.nih.gov.