MIT researchers have explained why two mutations in the H1N1 avian flu virus were critical for viral transmission in humans during the 1918 pandemic outbreak that killed at least 50 million people -believed more than that taken by the Black Death, and higher than the number killed in World War I.
The 1918 flu pandemic -commonly knownas the Spanish flu- was an
influenza pandemic that started in the United States, appeared in West
Africa and France and then spread to nearly every part of the globe in
three waves lasting from March 1918 to June 1920, spreading to the
Arctic and remote Pacific islands. It was caused by an unusually severe
and deadly Influenza A virus strain of subtype H1N1. In contrast to
most influenza outbreaks which predominantly affect juvenile, elderly,
or otherwise weakened patients, the Spanish Flue also claimed healthy
young adults, resulting from infection rates of up to 50% and the
extreme severity of the symptoms, suspected to be caused by cytokine
The disease was first discovered at Fort Riley, Kansasand Queens, New York , in 1918. In August 1918, a more virulent strain appeared simultaneously in Brest, France, in West Africa at Freetown, Sierra Leone, and in the U.S. at Boston, Massachusetts. The Allies of World War I came to call it the Spanish Flu, primarily because the pandemic received greater press attention after it moved from France to Spain in November of 1918.
The MIT team showed that the 1918 influenza strain developed two mutations in a surface molecule called hemagglutinin (HA), which allowed it to bind tightly to receptors in the human upper respiratory tract.
"Two mutations dramatically change the HA binding affinity to receptors found in the human upper airways," said Ram Sasisekharan, MIT's Underwood Prescott Professor of Biological Engineering and Health Sciences and Technology.
In January, Sasisekharan and colleagues reported in Nature Biotechnology that flu viruses can only bind to human respiratory cells if they match the shape of sugar (or glycan) receptors found on those cells.
The glycan receptors found in the human respiratory tract are known as alpha 2-6 receptors, and they come in two shapes-one resembling an open umbrella, and another resembling a cone. To infect humans the MIT team found that avian flu viruses must gain the ability to bind to the umbrella-shaped alpha 2-6 receptor.
In the current study, the team discovered that two mutations in HA allow flu viruses to bind tightly or with high affinity to the umbrella-shaped glycan receptors.
"The affinity between the influenza virus HA and the glycan receptors appears to be a critical determinant for viral transmission," said Sasisekharan.
The researchers used the 1918 influenza virus as a model system to
investigate the biochemical basis for hemagglutinin binding to glycans,
which leads to viral transmission.
This new work could aid researchers in monitoring the HA mutations in the H5N1 avian flu strains currently circulating in Asia. These mutations could enable the virus to jump from birds to humans, as many epidemiologists fear will occur.
Researchers from the Centers for Disease Control and Prevention reported on the varying infectiousness of these strains last year, but the PNAS study is the first that explains the exact biochemical reason underlying these differences.
Posted by Casey Kazan. Adapted from an MIT news release.
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