As flu related panics repeatedly circle the globe, just like the “Mexican wave” going around a soccer stadium, scientists are constantly prodded to look back at previous pandemics in order to feel that they could control future ones. At MIT, researchers have explained the mutation mechanism thanks to which the 1918 flu epidemic became the killer that it was.
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. They compared the virus that caused the 1918 pandemic (known as SC18) with a strain called NY18, which differs from SC18 by only one amino acid, and also the AV18 strain, which differs from SC18 by two amino acids.
Using ferrets (which are susceptible to human flu strains), researchers had earlier found that, while SC18 transmitted efficiently between ferrets, NY18 is only slightly infectious and AV18 not at all infectious.
These earlier findings correlate with the viruses’ ability to bind to umbrella-shaped alpha 2-6 glycan receptors, demonstrated in the current PNAS study.
NY18, which is only slightly infectious, binds to the umbrella-shaped alpha 2-6 receptors, but not as well as SC18, which is highly infectious.
AV18, which does not infect humans, does not have any affinity for the umbrella-shaped alpha 2-6 receptors and binds only to alpha 2-3 receptors.
Another strain, TX18, binds to alpha 2-6 and alpha 2-3 but, because it binds with high affinity to the umbrella-shaped alpha 2-6 receptors, is much more infectious than NY18.
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.