# 7370
We’ve a pair of avian flu studies, published today in the online journal Cell, that look at the current ability of both the H7N9 and H5N1 viruses to bind to human receptor cells.
While there may be other factors at play, the primary barrier that prevents these viruses from sparking a pandemic appears to be their preferential binding to avian receptor cells.
We’ve discussed receptor binding often in the past (see Study: Dual Receptor Binding H5N1 Viruses In China & PLoS: Human-Type H5N1 Receptor Binding In Egypt) but to review:
Flu Virus binding to Receptor Cells – Credit CDC
Human adapted influenza viruses have an RBS - Receptor Binding Site (the area of its genetic sequence that allows it to attach to, and infect, host cells) that – like a key slipping into a padlock -`fit’ the receptor cells commonly found in the human upper respiratory tract; the alpha 2,6 receptor cell.
Avian adapted flu viruses, like the H5N1 virus, bind preferentially to the alpha 2,3 receptor cells found in the gastrointestinal tract of birds.
While there are some alpha 2,3 cells deep in the lungs of humans, for an influenza to be successful in a human host, most researchers believe it needs to a able to bind to the a 2,6 receptor cell.
The $64 question that the research team lead by Ram Sasisekharan, the Alfred H. Caspary Professor of Biological Engineering at MIT, have endeavored to answer is: what type - and how many - changes would these viruses need in order to become more transmissible in humans?
And the authors suggest, it’s probably not a lot.
Particularly with the H7N9 virus.
Quick links to the abstracts to these two studies (both studies are, alas, behind pay walls), and then a look at the press release, that describes their findings.
Glycan Receptor Binding of the Influenza A Virus H7N9 Hemagglutinin
Cell, 06 June 2013
Copyright © 2013 Elsevier Inc. All rights reserved.
10.1016/j.cell.2013.05.034Authors
Kannan Tharakaraman, Akila Jayaraman, Rahul Raman, Karthik Viswanathan, Nathan W. Stebbins, David Johnson, Zachary Shriver, V. Sasisekharan, Ram Sasisekharan
Highlights
- The hemagglutinin of H7N9 virus does not efficiently bind human receptors
- A single residue change in receptor binding site increases binding to human receptors
- Mutations on hemagglutinin may reduce the effectiveness of current H7 vaccines
Structural Determinants for Naturally Evolving H5N1 Hemagglutinin to Switch Its Receptor Specificity
Cell, 06 June 2013
Copyright © 2013 Elsevier Inc. All rights reserved.
10.1016/j.cell.2013.05.035Authors
Kannan Tharakaraman, Rahul Raman, Karthik Viswanathan, Nathan W. Stebbins, Akila Jayaraman, Arvind Krishnan, V. Sasisekharan, Ram Sasisekharan
Highlights
- Hallmark mutations do not switch receptor preference of recent H5 strains
- Structural comparison of H5 and H2 hemagglutinin receptor complexes
- Determination of key H5Nl receptor-binding features needed for quantitative switch
- Recent strains may require a single base pair change to switch receptor preference
While the full text of the articles are behind a pay wall, we do have a press release from MIT that tells us, in general terms, what these studies found. A few excerpts below, but follow the link to read it in its entirety.
Keeping an eye on bird flu
June 6, 2013
MIT studies of two influenza viruses reveal genetic mutations that could result in pandemic flu.
Anne Trafton, MIT News Office
(EXCERPTS)
New research from MIT shows that two recently emerged bird flu strains, which do not spread easily now, could become much more infectious with just one or a few genetic mutations.
The studies, which focused on the H5N1 and H7N9 flu strains, should help public health officials monitor evolving flu viruses for potential human-to-human transmission. They could also guide the development of new vaccines, says Ram Sasisekharan, the Alfred H. Caspary Professor of Biological Engineering and senior author of two papers appearing in the June 6 online edition of the journal Cell.
<SNIP>
H5N1
In the new Cell paper, the MIT team studied the structure of HA proteins from hundreds of H5N1 strains and identified three HA regions where one or two mutations would enable the HA to bind efficiently to human receptors. Most of these regions affect the base of the receptor-binding site.
The researchers also found that H5N1 has been evolving rapidly since 2005, but none of the current strains have all of the mutations needed to spread from human to human. However, the researchers found one strain that needs only a single amino-acid switch to become highly infectious, and several others that need only two. “There are multiple different ways that this can happen,” says Sasisekharan, who is also a member of MIT’s Koch Institute for Integrative Cancer Research.
Furthermore, because of all of the viral evolution that has occurred since 2005, the H5N1 vaccines that governments have stockpiled would probably no longer be effective, Sasisekharan says. “There is cause for concern,” he says. “Yet these findings open opportunities to make sure that some of these newer strains do become part of the stockpiling, because they are closer to human adaptation.”
H7N9
H7N9 has infected at least 132 people this year, mostly in China, and there have been 37 deaths, according to the World Health Organization — a lower fatality rate than that of the H5N1 virus.
The MIT researchers found that although the current circulating forms of H7N9 bind weakly to human receptors, a change in just one amino acid would dramatically increase the HA protein’s binding strength. “It was not a marginal increase; we saw a pretty significant increase in receptor binding,” Sasisekharan says.
“Our research provides insights to help keep track of potentially important mutations so that proactive steps can be taken to be better prepared against dangerous viruses.”
Whether any avian influenza strain can make the right changes, and become a human pandemic strain, remains a mystery.
Yesterday, in a NEJM Perspective, David M. Morens, M.D., Jeffery K. Taubenberger, M.D., Ph.D., and Anthony S. Fauci, M.D. wrestled with this problem in:
Pandemic Influenza Viruses — Hoping for the Road Not Taken
This remains one of the great debates in influenza science - and the question will likely only be settled after one finally does.
