Wednesday, November 19, 2014

mBio: Not All LPAI Flu Subtypes Are Created Equally


Credit NIAID



# 9343


Until avian H7N9 showed up a couple of years ago, LPAI (Low Pathogenic Avian Influenza) in birds was considered to constitute a minor human health threat, and our concerns were mostly they would evolve into HPAI (highly pathogenic) strains – with most of that concern focused on H5 and H7 subtypes.


H7N9 showed us that an avian influenza could be LPAI in birds and yet extremely pathogenic in humans.

Furthermore, in the summer of 2013 Taiwan reported the first known human infection with an avian H6N1 virus, and a few months later mainland China reported the first three cases of H10N8 (two fatal), further widening the range of avian subtypes capable of causing serious illness in humans.


Suddenly, there seemed to be more to keep an eye on than just HPAI H5 and H7.


All of which brings us to a fascinating study, published yesterday in the open-access journal mBio, that attempts to compare the pathogenicity of different HA Subtype LPAI flu strains in mammals, and finds some subtypes are far more virulent than others.

Researchers constructed identical LPAI avian flu viruses – differing each only by their hemagglutinin protein (H1-H16) - and tested them in mice and against human cell cultures.

They found the H1, H6, H7, H10, and H15 HA genes demonstrated enhanced virulence in mice and were destructive to human bronchial epithelial cells (in vitro), while chimeric H2, H3, H5, H9, H11, H13, H14 and H16 subtypes caused no significant disease.


Leading the study is noted NIAID virologist Jeffrey Taubenberger, who was the first to sequence the the genome of the 1918 Spanish Flu virus.  First some excerpts from the mBio article (follow the link to read in its entirety), followed by a link and excerpt from the press release.


Contemporary Avian Influenza A Virus Subtype H1, H6, H7, H10, and H15 Hemagglutinin Genes Encode a Mammalian Virulence Factor Similar to the 1918 Pandemic Virus H1 Hemagglutinin

Li Qia, Lindsey M. Pujanauskia, A. Sally Davisa, Louis M. Schwartzmana, Daniel S. Chertowa,b,  David Baxterc, Kelsey Scherlerc, Kevan L. Hartshornd,  Richard D. Slemonse,  Kathie-Anne Waltersc,  John C. Kasha,  Jeffery K. Taubenbergera


Zoonotic avian influenza virus infections may lead to epidemics or pandemics. The 1918 pandemic influenza virus has an avian influenza virus-like genome, and its H1 hemagglutinin was identified as a key mammalian virulence factor. A chimeric 1918 virus expressing a contemporary avian H1 hemagglutinin, however, displayed murine pathogenicity indistinguishable from that of the 1918 virus. Here, isogenic chimeric avian influenza viruses were constructed on an avian influenza virus backbone, differing only by hemagglutinin subtype expressed. Viruses expressing the avian H1, H6, H7, H10, and H15 subtypes were pathogenic in mice and cytopathic in normal human bronchial epithelial cells, in contrast to H2-, H3-, H5-, H9-, H11-, H13-, H14-, and H16-expressing viruses. Mouse pathogenicity was associated with pulmonary macrophage and neutrophil recruitment. These data suggest that avian influenza virus hemagglutinins H1, H6, H7, H10, and H15 contain inherent mammalian virulence factors and likely share a key virulence property of the 1918 virus. Consequently, zoonotic infections with avian influenza viruses bearing one of these hemagglutinins may cause enhanced disease in mammals.

IMPORTANCE Influenza viruses from birds can cause outbreaks in humans and may contribute to the development of pandemics. The 1918 pandemic influenza virus has an avian influenza virus-like genome, and its main surface protein, an H1 subtype hemagglutinin, was identified as a key mammalian virulence factor. In a previous study, a 1918 virus expressing an avian H1 gene was as virulent in mice as the reconstructed 1918 virus. Here, a set of avian influenza viruses was constructed, differing only by hemagglutinin subtype. Viruses with the avian H1, H6, H7, H10, and H15 subtypes caused severe disease in mice and damaged human lung cells. Consequently, infections with avian influenza viruses bearing one of these hemagglutinins may cause enhanced disease in mammals, and therefore surveillance for human infections with these subtypes may be important in controlling future outbreaks.

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From the  American Society for Microbiology we get the following press release:


Some flu viruses potentially more dangerous than others

WASHINGTON, DC - November 18, 2014 - Certain subtypes of avian influenza viruses have the potential to cause more severe disease in humans than other avian influenza subtypes and should be monitored carefully to prevent spread of disease, according to a study published this week in mBio®, the online open-access journal of the American Society for Microbiology.

The work, directed by researchers at the National Institute of Allergy and Infectious Diseases in Bethesda, Md., found that flu viruses expressing the low pathogenicity avian H1, H6, H7, H10 or H15 hemagglutinins (genes that encode the major surface protein for the virus) led to fatal infections in mice and caused more cell damage in normal human lung cells grown in culture as compared to avian influenza viruses with other subtypes. The 1918 H1 subtype hemagglutinin has been already identified as a key virulence factor in the pandemic influenza virus of 1918. That virus, which caused the so-called "Spanish flu," spread rapidly around the world, resulting in approximately 50 million deaths.

"Viruses with these avian hemagglutinins have some type of inherent virulence motif to them, in that they induce a marked inflammatory response in mammals including human cells in culture," said senior study author Jeffery K. Taubenberger, MD, PhD, chief of the Viral Pathogenesis and Evolution Section of NIAID's Laboratory of Infectious Diseases. In 2013-2014 there have been close to 400 cases of avian influenza H7N9 infections in people in China, many severe, along with small numbers of severe human infections with H10N8 and H6N1 subtypes. "From a public health and epidemiology standpoint, it's useful to know that avian viruses of these subtypes (for example, H6, H7, or H10) might lead to more severe infections in humans and is something to look out for."

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