Flu clue: NMR spectroscopy and 1918

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  • Published: Oct 1, 2015
  • Author: David Bradley
  • Channels: NMR Knowledge Base
thumbnail image: Flu clue: NMR spectroscopy and 1918


Chad Petit, Ph.D., (back left) discusses data with graduate students Alexander “Alex” Kleinpeter and Alexander Jureka (sitting) at the Central Alabama High-Field Nuclear Magnetic Resonance Facility, which is housed in the Department of Chemistry, UAB College of Arts and Sciences. Two of the NMR machines are visible in the background.

Nuclear magnetic resonance spectroscopy has led to new clues regarding the particularly virulent behaviour of the influenza virus that caused tens of millions of deaths at the end of World War I.

Each year influenza strikes about 3 to 5 million people with severe illness and kills up to half a million. This is an enormous burden on humanity, but periodically, a much more virulent strain will emerge such as the one we tend to refer to as “Spanish flu" that infected a third of the world’s population in 1918 and killed an estimated 50 to 100 million people. Clues about what made the 1918 influenza virus so dangerous, whether another might occur that kills people on the same scale and what we might do about it before that happens, is the focus of intense research.

Now, Chad Petit of the University of Alabama at Birmingham, Alabama, USA and colleagues have revealed a new interaction that might one day be exploited as a target for new antiviral drugs to fight virulent strains of influenza. Petit’s team carried out in vitro experiments to show that a non-structural protein, NS1, from the 1918 flu virus binds directly to the human cytoplasmic protein RIG-I (retinoic acid-inducible gene 1), which is a pattern recognition receptor for detecting influenza A, Sendai virus, flavivirus and other viruses and as such is considered to be a key trigger of the human immune system's response to infection by flu. Further research is needed to see whether this binding process has a physiological effect in inhibiting the immune response, although that is the suspicion.


It is known that NS1 is expressed rapidly by a virulent flu virus as it invades the host animal's cells, helping the virus wheedle its way around the immune system by interfering with receptor proteins including RIG-1. Petit and his colleagues at UAB are the first to show that NS1 has a direct interaction with RIG-I. Moreover, the function of that portion of the 1918 NS1 RNA binding domain that connects with RIG-I was not known before.

“NS1 is almost like the Swiss army knife of proteins because it has so many functions,” Petit explains. He adds that NS1 appears to interact with 20 to 30 host proteins. Compared with other flu proteins, NS1 also has remarkable genetic plasticity, meaning that its effect on virulence can vary among strains. The team also tested NS1 from the influenza A/Udorn/1972 strain  and found that this protein was unable to bind to RIG-I. A comparison of the two structures led them to the binding site for 1918 NS1 and thence revealed the differences in amino acid sequence that made 1918 different from 1972 and so lays some of the blame for its virulence on the difference in RIG-1 binding ability.

Function and form

“One of NS1’s main functions is to combat the immune system, and without NS1, the host immune response quickly takes out the virus,” Petit explains. “But I find that there’s not a lot of data that compares NS1 from strain to strain in the same kind of test.”

The team carried out their solution structure and binding studies using NMR at UAB’s Central Alabama High-Field Nuclear Magnetic Resonance Facility, with clones of the relevant domains from the NS1 and RIG-I proteins. The study not only revealed functionality for the novel RIG-I binding site found on the 1918 opposite the RNA binding interface but revealed two potential salt bridges that are present in the 1918 protein but absent in the 1972 Udorn. These salt bridges seem to change the 1918 protein structure significantly, increasing the average intramolecular distance between two of the protein helices, which could underlie the strain-specific nature of the interaction of 1918 NS1RBD with RIG-I.

Petit told SpectroscopyNOW that, "The next step in our research is to determine how this interaction modulates influenza virulence and pathogenicity in the context of the virus. Ultimately, we would like to identify targets for the future development of novel anti-influenza pharmaceuticals. Additionally, we also would like to identify virulence markers to inform surveillance efforts designed to predict influenza virulence from sequence data alone."

Related Links

Structure 2015, online: "Structural basis for a novel interaction between the NS1 protein derived from the 1918 influenza virus and RIG-I"

Article by David Bradley

The views represented in this article are solely those of the author and do not necessarily represent those of John Wiley and Sons, Ltd.

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