Credit CDC PHIL
# 6975
A study today - authored by Hassan Zaraket, Olga A. Bridges, Charles J. Russell - links a single mutation (lysine-to-isoleucine at position 58 in the H5N1 HA2 subunit) to increased replication in mice.
And not by just a little . . . by a hundred fold or better.
The study, which is scheduled to be formally published in the May issue of the Journal of Virology , can be accessed at the following link:
The pH of Activation of the Hemagglutinin Protein Regulates H5N1 Influenza Virus Replication and Pathogenesis in Mice
Hassan Zaraket, Olga A. Bridges, Charles J. Russell5
Department of Infectious Diseases, St. Jude Children's Research Hospital
Department of Microbiology, Immunology & 8 Biochemistry, College of Medicine, The University of Tennessee Health Science Center
This is a fairly technical paper, and so non-virologists who find it tough sledding may wish to move on to the accompanying editorial and the press release.
The editorial, which is somewhat less daunting, is available at:
A New Determinant of H5N1 Influenza Virus Pathogenesis in Mammals
Terence S. Dermody, Rozanne M. Sandri-Goldin, and Thomas Shenk
This study involved doing work with a recombinant H5N1 virus that produces enhanced virulence in mice. Therefore, a good deal of this editorial addresses the steps taken to minimize the risks, DURC (Duel Use Research of Concern) compliance, and the ultimate decision to publish the results.
Note: These researchers did not seek to increase the virus’s transmissibility, only gauge its replication and mortality in a mammalian species.
This editorial lists benefits from this type of research that include: by identifying which genetic changes favor a lower pH optimum of HA activation, it may be possible to identify which strains are the most dangerous to humans.
Additionally, introducing a mutation that increases replication into a H5N1 vaccine seed strain could conceivably speed up vaccine production.
Obviously aware that the publication of this study might raise some eyebrows in the biosecurity world, the authors of the accompanying editorial conclude by writing:
Reasonable people may disagree about whether the work reported by Zaraket et al. (1) is DURC. We note that a designation of DURC should not necessarily preclude conduct of the research or communication of the findings.
The study in this issue of JVI was thoughtfully considered by experts in influenza virus research, biosafety and biosecurity, scientific publication, and the U.S. government.
Following this consideration, we concluded that the benefits of publication outweigh any potential risks. Given the concerns raised about the possibility of DURC in this study, we think that describing the process used to evaluate the manuscript is an important
The following press release from American Society for Microbiology provides us with the easiest layman’s explanation (once you get past the title) for what was done, and what it means.
Mutation altering stability of surface molecule in acid enables H5N1 infection of mammals
A single mutation in the H5N1 avian influenza virus that affects the pH at which the hemagglutinin surface protein is activated simultaneously reduces its capacity to infect ducks and enhances its capacity to grow in mice according to research published ahead of print today in the Journal of Virology.
"Knowing the factors and markers that govern the efficient growth of a virus in one host species, tissue, or cell culture versus another is of fundamental importance in viral infectious disease," says Charles J. Russell of St. Jude Children's Research Hospital, Memphis, TN, an author on the study. "It is essential for us to identify influenza viruses that have increased potential to jump species, to help us make decisions to cull animals, or quarantine humans." The same knowledge "will help us identify targets to make new drugs that stop the virus… [and] engineer vaccines."
<SNIP>
When influenza viruses infect birds, the hemagglutinin surface protein of the virus is activated by acid in the entry pathway inside the host cell, enabling it to invade that cell. In earlier work, Russell and collaborators showed that a mutant version of the influenza H5N1 virus called K58I that resists acid activation, loses its capacity to infect ducks. Noting that the upper airways of mammals are more acidic than infected tissues of birds, they hypothesized, correctly, that a mutation rendering the hemagglutinin protein resistant to acid might render the virus more infective in mammals.
In this study the investigators found that K58I grows 100-fold better than the wild-type in the nasal cavities of mice, and is 50 percent more lethal. Conversely, the mutant K58I virus failed completely to kill ducks the investigators infected, while the wild-type killed 66 percent of ducks, says Russell. "A single mutation that eliminates H5N1 growth in ducks simultaneously enhances the capacity of H5N1 to grow in mice. We conclude that enhanced resistance to acid inactivation helps adapt H5N1 influenza virus from an avian to a mammalian host.
"These data contribute new information about viral determinants of influenza virus virulence and provide additional evidence to support the idea that H5N1 influenza virus pathogenesis in birds and mammals is linked to the pH of [hemagglutinin] activation in an opposing fashion," Terence S. Dermody of Vanderbilt University et al. write in an editorial in the journal accompanying the paper. "A higher pH optimum of [hemagglutinin] activation favors virulence in birds, whereas a lower pH optimum… favors virulence in mammals."
Based on this and another study, "…surveillance should include phenotypic assessment of the [hemagglutinin] activation pH in addition to sequence analysis," Dermody writes.
The journal carefully considered whether to publish the paper, because it raised issues of "dual use research of concern" (DURC), writes Dermody. DURC is defined as "Life sciences research that, based on current understanding, can be reasonably anticipated to provide knowledge, information, products, or technologies that could be directly misapplied to pose a significant threat with broad potential consequences to public health and safety, agricultural crops and other plants, animals, the environment, materiel, or national security," according to a US government policy document.
However, both the National Institute of Allergy and Infectious Diseases and the St. Jude Institutional Biosafety Committee concluded that the study failed to meet the definition of DURC. Clinching the case, "the addition of the key mutation in the Russell paper to other previously reported mutations would not result in an even more virulent H5N1 influenza virus," says Dermody.
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