I had the flu once. Just once. It was horrible. There was no coughing, no sneezing, little to none of the typical common cold symptoms. There was just pain, fever, and misery. Complete and utter misery for a week straight. Many people call their severe colds the flu, but they are mistaken – the former is caused by the relatively mild rhinovirus, while the latter is the havoc wreaked by the influenza virus – which I am slightly obsessed with, and am writing about for the second time.
The flu is far more unpleasant than the common cold and luckily, there is a vaccine. Unluckily, this vaccine is not always fully effective and takes a lot of (educated) guess work to design. So begins a recent paper by Sui et al. in Nature Structural and Molecular Biology, the result of a collaboration between investigators at the Dana Farber Cancer Institute in Boston, the Centers for Disease Control in Atlanta, and the Burnham Institute in La Jolla. From first glance, I could tell that this is one of the best-written papers I have come across in a long time. It was a pleasure to read, and is now a pleasure to relate.
The authors took a brute force screening approach to identifying human antibodies which could neutralize influenza virus. They had previously constructed a library of antibodies derived from 57 people – this library numbered over 27 billion individual antibodies. They then applied this library of antibodies to an immobilized influenza hemagglutinin (HA) trimer, the viral protein responsible for binding and entry of the viral particle into host cells. From the huge screen, 10 antibodies were identified and further characterized. Based on neutralization potency, the field was further narrowed to three unique antibodies which recognized similar sites on the HA trimer. These antibodies were found to protect mice against influenza infection and to prevent the spread of the virus post-infection, likely by preventing entry, but not binding, of the virus into the host cell.
Once of the neutralizing antibodies was crystallized along with an HA trimer, the mechanism of inhibition became clear – the heavy chain of the antibody bound near the HA fusion peptide, the portion of HA necessary for fusion. This in itself would not be earth shattering. The really cool part of this finding is that the part of HA bound by the neutralizing antibody is highly conserved among different strains of influenza – it is so important to the virus that it hardly ever mutates, maintaining the same amino acid sequence and likely, conformation, throughout the antigenic shift and drift that characterizes the influenza virus. Basically, this antibody sticks to influenza’s Achilles heel, one that can’t shake off the antibody by mutating, for fear of negatively impacting the virus itself. The same antibody can potentially prevent infection by most (though not all) different versions of influenza. Combined with a small molecule inhibitor, this antibody could serve as the universal vaccine from all misery-inducing strains of the flu. That’s a ways off yet, but the promise is oh so sweet, especially once you have experienced the real flu for yourself.
Sui, J., Hwang, W., Perez, S., Wei, G., Aird, D., Chen, L., Santelli, E., Stec, B., Cadwell, G., Ali, M., Wan, H., Murakami, A., Yammanuru, A., Han, T., Cox, N., Bankston, L., Donis, R., Liddington, R., & Marasco, W. (2009). Structural and functional bases for broad-spectrum neutralization of avian and human influenza A viruses Nature Structural & Molecular Biology, 16 (3), 265-273 DOI: 10.1038/nsmb.1566
one century ago, one caught by flu may probably be exterminated! Nowadays, one plagued by cancer in terminal will still enjoy the hope to survive!
Imagine what will inflict human being in one century from the perspective of evolution!
Excellent stuff Anna – I’ll check out the paper for myself (did you think about linking through to ResearchBlogging?). It sounds like a very exciting finding but I wouldn’t under-estimate the capacity of the virus to find a way to resist the attentions of these particular antibodies. They’re devilishly clever…
Wenhua – I am scared to think of it. Prions seem to be the new wave of infectious agents. There is no cure or treatment for those types of infections, so I shudder to think how much worse it could get!
Stephen – The authors passaged influenza in the presence of the neutralizing Ab but failed to isolate neutralization escape mutants. They only went three passages out, so there is the possibility that the virus could still adapt. It looks pretty promising though. Thanks for the Research Blogging suggestion! Will do.
Anna> a very nice summary about the paper!
Influenza is still a major player in the world of death though… not to scare you, but it is on the top 5 and especially looking at children and older people.
Personally, I might be more scared of the parasites (not really related to death numbers, it just makes me really freaked out thinking about bot flies and Leishmania and other bigger “microbes” that live in your body….). I guess that is why I always fancied that cold north Europe part of the world ;)
This paper reminds me of the work by a Belgian team of scientists at Ghent University. About 10 years ago they reported in Nature Medicine the creation of a universal Influenza A vaccine based on the external domain of the viral M2-protein (Neirynck S. Nature Medicine 1999). Since the M2 amino acid sequence is highly conserved between influenza A strains the resulting vaccine protects against a broad array of viral strains. Basically, a single vaccination is expected to yield long-lasting protection against most (if not all) influenza A strains. A successful phase I clinical trial was recently completed.
It is unfortunate that Sui et al. failed to mention this in their paper.
Anna, a question for U!
Concerning prion, I have been wondering that how prion can pass through BLOOD Brain Barrier(BBB) without any davastaing damages to physical function immediately!
However, PrPc seem to be versatile in functioning to acts like a TRANSFORMER! HAHH!