tetano
Editor, Senior Moderator
Published online before print January 25, 2016, doi: 10.1073/pnas.1524384113
PNAS January 25, 2016
[h=1]Molecular requirements for a pandemic influenza virus: An acid-stable hemagglutinin protein[/h]
[h=2]Significance[/h] Influenza pandemics occur several times per century, causing millions of deaths. For one of the myriad of zoonotic influenza viruses to do so, a virus containing a hemagglutinin (HA) surface antigen previously unseen by most humans must evolve the necessary, albeit largely unknown, properties for sustained respiratory spread between people. During entry, the prototypic viral fusion protein HA binds receptors and is triggered irreversibly by low pH in endosomes to cause membrane fusion. These studies link a fundamental property, activation energy of a fusion protein measured as its pH of activation (acid stability), to the ability of zoonotic influenza viruses to cause a human pandemic. Monitoring HA stability is expected to enhance prepandemic surveillance and control of emerging influenza viruses.
[h=2]Abstract[/h] Influenza pandemics require that a virus containing a hemagglutinin (HA) surface antigen previously unseen by a majority of the population becomes airborne-transmissible between humans. Although the HA protein is central to the emergence of a pandemic influenza virus, its required molecular properties for sustained transmission between humans are poorly defined. During virus entry, the HA protein binds receptors and is triggered by low pH in the endosome to cause membrane fusion; during egress, HA contributes to virus assembly and morphology. In 2009, a swine influenza virus (pH1N1) jumped to humans and spread globally. Here we link the pandemic potential of pH1N1 to its HA acid stability, or the pH at which this one-time-use nanomachine is either triggered to cause fusion or becomes inactivated in the absence of a target membrane. In surveillance isolates, our data show HA activation pH values decreased during the evolution of H1N1 from precursors in swine (pH 5.5?6.0), to early 2009 human cases (pH 5.5), and then to later human isolates (pH 5.2?5.4). A loss-of-function pH1N1 virus with a destabilizing HA1-Y17H mutation (pH 6.0) was less pathogenic in mice and ferrets, less transmissible by contact, and no longer airborne-transmissible. A ferret-adapted revertant (HA1-H17Y/HA2-R106K) regained airborne transmissibility by stabilizing HA to an activation pH of 5.3, similar to that of human-adapted isolates from late 2009?2014. Overall, these studies reveal that a stable HA (activation pH ≤ 5.5) is necessary for pH1N1 influenza virus pathogenicity and airborne transmissibility in ferrets and is associated with pandemic potential in humans.
http://www.pnas.org/content/early/2016/01/20/1524384113
PNAS January 25, 2016
[h=1]Molecular requirements for a pandemic influenza virus: An acid-stable hemagglutinin protein[/h]
- Marion Russier[SUP]a[/SUP],
- Guohua Yang[SUP]a[/SUP],
- Jerold E. Rehg[SUP]b[/SUP],
- Sook-San Wong[SUP]a[/SUP],
- Heba H. Mostafa[SUP]a[/SUP],
- Thomas P. Fabrizio[SUP]a[/SUP],
- Subrata Barman[SUP]a[/SUP],
- Scott Krauss[SUP]a[/SUP],
- Robert G. Webster[SUP]a[/SUP],[SUP]1[/SUP],
- Richard J. Webby[SUP]a[/SUP],[SUP]c[/SUP], and
- Charles J. Russell[SUP]a[/SUP],[SUP]c[/SUP],[SUP]1[/SUP]
- [SUP]a[/SUP]Department of Infectious Diseases, St. Jude Children?s Research Hospital, Memphis, TN 38105;
- [SUP]b[/SUP]Department of Pathology, St. Jude Children?s Research Hospital, Memphis, TN 38105;
- [SUP]c[/SUP]Department of Microbiology, Immunology & Biochemistry, College of Medicine, University of Tennessee Health Science Center, Memphis, TN 38163
- Contributed by Robert G. Webster, December 14, 2015 (sent for review October 13, 2015; reviewed by Wendy Barclay, Robert A. Lamb, and Kanta Subbarao)
[h=2]Significance[/h] Influenza pandemics occur several times per century, causing millions of deaths. For one of the myriad of zoonotic influenza viruses to do so, a virus containing a hemagglutinin (HA) surface antigen previously unseen by most humans must evolve the necessary, albeit largely unknown, properties for sustained respiratory spread between people. During entry, the prototypic viral fusion protein HA binds receptors and is triggered irreversibly by low pH in endosomes to cause membrane fusion. These studies link a fundamental property, activation energy of a fusion protein measured as its pH of activation (acid stability), to the ability of zoonotic influenza viruses to cause a human pandemic. Monitoring HA stability is expected to enhance prepandemic surveillance and control of emerging influenza viruses.
[h=2]Abstract[/h] Influenza pandemics require that a virus containing a hemagglutinin (HA) surface antigen previously unseen by a majority of the population becomes airborne-transmissible between humans. Although the HA protein is central to the emergence of a pandemic influenza virus, its required molecular properties for sustained transmission between humans are poorly defined. During virus entry, the HA protein binds receptors and is triggered by low pH in the endosome to cause membrane fusion; during egress, HA contributes to virus assembly and morphology. In 2009, a swine influenza virus (pH1N1) jumped to humans and spread globally. Here we link the pandemic potential of pH1N1 to its HA acid stability, or the pH at which this one-time-use nanomachine is either triggered to cause fusion or becomes inactivated in the absence of a target membrane. In surveillance isolates, our data show HA activation pH values decreased during the evolution of H1N1 from precursors in swine (pH 5.5?6.0), to early 2009 human cases (pH 5.5), and then to later human isolates (pH 5.2?5.4). A loss-of-function pH1N1 virus with a destabilizing HA1-Y17H mutation (pH 6.0) was less pathogenic in mice and ferrets, less transmissible by contact, and no longer airborne-transmissible. A ferret-adapted revertant (HA1-H17Y/HA2-R106K) regained airborne transmissibility by stabilizing HA to an activation pH of 5.3, similar to that of human-adapted isolates from late 2009?2014. Overall, these studies reveal that a stable HA (activation pH ≤ 5.5) is necessary for pH1N1 influenza virus pathogenicity and airborne transmissibility in ferrets and is associated with pandemic potential in humans.
http://www.pnas.org/content/early/2016/01/20/1524384113