How Influenza Gains its Airborne Transmissibility

The soft palate — the soft tissue at the back of the roof of the mouth — plays a key role in the flu viruses’ ability to travel through the air. In this illustration, the soft palate is highlighted red. In the background are renderings of the flu virus. [Jose-Luis Olivares/MIT. Flu Virus illustrations courtesy of National Institute of Allergy and Infectious Diseases/NIH.]

Understanding the molecular underpinnings of how the influenza virus gains the ability to spread rapidly is critical in controlling outbreaks of the disease. Now, scientists at the Massachusetts Institute of Technology (MIT) and National Institute of Allergy and Infectious Diseases (NIAID) believe they have discovered why some flu strains are better equipped at spreading from person to person. The new data suggests that the soft palate— the soft tissue at the back of the roof of the mouth—plays a key role in the viruses’ transmissibility.

The investigators from MIT and NIAID made the unexpected discovery while examining the H1N1 flu strain, which caused a 2009 pandemic that killed more than 250,000 people. 

Researchers had shown previously that airborne transmissibility depends on whether the virus’ hemagglutinin (HA) protein can bind to a specific type of receptor on the surface of human respiratory cells. Some flu viruses bind better to α2,6 glycan receptors, which are found primarily in humans and other mammals, while other viruses are better adapted to α2,3 glycan receptors, found predominantly in birds. 

Interestingly, the 2009 H1N1 strain was very good at binding to human α2,6 receptors. However, in the new study, the researchers made four genetic mutations in the HA gene of the 2009 H1N1 strain, which made it better suited to bind α2,3 receptors instead of α2,6. Subsequently, they infected ferrets, which are often used to model human influenza infection, with the mutated strain.

The researchers hypothesized that the mutated virus would not spread, but to their disbelief, it was transmitted through the air just as well as the original version of the virus. The authors sequenced the transmitted virus’ genetic material and found that it had undergone a genetic reversion that allowed the HA protein to bind to α2,6 glycan receptors as well as α2,3 glycan receptors.

“This is an experimental validation that gain of binding to the α2,6 glycan receptor is critical for aerosol transmission,” explained co-senior author Ram Sasisekharan, Ph.D., professor of biological engineering and health sciences and technology at MIT.

The findings from this study were published recently online in Nature through an article entitled “The soft palate is an important site of adaptation for transmissible influenza viruses.”

Consequently, the investigators examined tissue from different parts of the ferrets’ respiratory tract and found that viruses with the genetic reversion were most abundant in the soft palate. By three days after the initial infection, 90% of the viruses in this region had the reverted form of the virus. Other sites in the respiratory tract had a mix of the two types of virus.

Currently, the MIT and NIAID teams are trying to figure out how this reversion occurs, and why it happens in the soft palate. Yet, since the researchers have confirmed that viruses with the ability to bind to both α2,6 and α2,3 glycan receptors can spread effectively among mammals, they can use that information to help identify viruses that may cause pandemics,

“It really provides us with a handle to very systematically look at any evolving pandemic viruses from the point of view of their ability to gain airborne transmissibility through binding to these α2,6 glycan receptors,” Dr. Sasisekharan stated.

Dr. Sasisekharan and his colleagues surmise that flu viruses with greater ability to transmit through the air can outcompete other viruses in the soft palate—where the can spread by packaging themselves into mucus droplets produced by cells in the soft palate.

“We have identified the previously overlooked soft pallet as an important site of isolation of transmissible virus and perhaps the initial site of infection. Analysis of the replicative fitness of influenza A virus in this tissue may be warranted in assessment of their pandemic potential,” the authors concluded.