LA JOLLA, Calif.—Researchers at the Scripps Research Institute have detailed the structure of a protein from the H1N1 swine flu virus that triggered last year's pandemic. Comparing the virus responsible for the 2009 outbreak to a range of different human H1N1 flu viruses from the early 20th century, the team of scientists says their work may explain why some older individuals were less susceptible to the recent outbreak than younger ones—a finding the researchers say may lend some insight into how scientists and public health officials can respond to future pandemics.
Publishing their findings in the March 25 issue of Science Express, the researchers detail the structure of the hemagglutinin, the main antigenic determinant on the virus which also enables the virus to infect cells of the host organism, from 2009's H1N1 swine flu virus.
Working with scientists at Mount Sinai School of Medicine, who provided a clone of the major surface antigen from the emerging virus, A/California/04/2009 (CA04), the team used X-ray crystallography to produce quantities of the viral protein and crystallized it. They then placed the crystal in front of a beam of X-rays, which diffract when they strike the atoms in the crystal. Based on the pattern of diffraction, scientists can reconstruct the shape of the original molecule.
Knowing that vulnerability to an individual influenza infection depends on how well a person's immune system recognizes the hemagglutinin, the scientists compared the 2009 hemagglutinin protein with the hemagglutinin from all known human H1N1 strains between 1918 and 1957, and representative strains since 1977. The researchers found that while much of the hemagglutinin three-dimensional structure had been maintained among the different viruses, the amino acids (protein building blocks) on the viral surface were substantially different in the 2009 virus from seasonal strains. This could enable the virus to initially evade detection by the immune system.
Notably, the team also found that one area of the hemagglutinin, called antigenic site Sa, was highly similar between the 2009 and the 1918 viruses. The similarity of the Sa site for the two viruses suggested that some individuals might be able to mount an immune response that could neutralize either virus.
"Parts of the 2009 virus are remarkably similar to human H1N1 viruses circulating in the early 20th century," says Scripps Research professor Ian Wilson, the senior author of the study. "Our findings provide strong evidence that exposure to earlier viruses has helped to provide some people with immunity to the recent influenza pandemic."
At the same time as this discovery, another flu project in Wilson's lab was working to determine the structure of the antibody 2D1 that neutralized the 1918 influenza virus. The antibody had been isolated from a survivor of the 1918 Spanish flu. Researchers at Vanderbilt University, who have been collaborating with Wilson's lab, recently published an article in the Journal of Virology that showed mice challenged with the 2009 virus are protected by the administration of the antibody against the 1918 virus. Wilson's current study shows that prior exposure to viruses that were around decades ago can provide some protection against infection against a newly emerging pandemic.
The information should be useful for scientists and public health officials as they respond to current and future pandemics, Wilson says.
"It brings into question how we deal with vaccinations," Wilson says. It suggests that we should think differently about vaccination strategies for viruses that disappear for a while, but are resident in pigs and wild birds, because they can drift off and wait long enough for people to lose their heteroimmunity to the virus that started the whole pandemic strain."
Other authors of the paper, "Structural basis of pre-existing immunity to the 2009 H1N1 pandemic influenza virus," include Rui Xu, a research associate in Wilson's lab, who was first author of the paper with graduate student Damian Ekiert, also of the Wilson lab; Jens C. Krause and James E. Crowe Jr. of Vanderbilt University Medical Center; and Rong Hai of the Mount Sinai School of Medicine.
The work was supported by the National Institutes of Health (NIH), the Skaggs Institute for Chemical Biology, and predoctoral fellowships from the Achievement Rewards for College Scientists Foundation and the NIH Molecular Evolution Training Program. X-ray diffraction datasets were collected at the Stanford Synchrotron Radiation Lightsource and the Advanced Photon Source, which are supported by NIH and the U.S. Department of Energy.
This image, from the Scripps Research Wilson lab, shows part of the 1918 Spanish flu virus in complex with an antibody that also neutralizes the 2009 "swine flu" virus. The antibody 2D1 Fab is depicted as red and yellow ribbons. The hemagglutinin on the flu virus is depicted as a solid surface. One of the three hemagglutinin subunits is highlighted in blue and cyan. The Sa site—the region conserved between the 1918 and swine flu viruses and targeted by the 2D1 antibody—is highlighted in magenta.
Publishing their findings in the March 25 issue of Science Express, the researchers detail the structure of the hemagglutinin, the main antigenic determinant on the virus which also enables the virus to infect cells of the host organism, from 2009's H1N1 swine flu virus.
Working with scientists at Mount Sinai School of Medicine, who provided a clone of the major surface antigen from the emerging virus, A/California/04/2009 (CA04), the team used X-ray crystallography to produce quantities of the viral protein and crystallized it. They then placed the crystal in front of a beam of X-rays, which diffract when they strike the atoms in the crystal. Based on the pattern of diffraction, scientists can reconstruct the shape of the original molecule.
Knowing that vulnerability to an individual influenza infection depends on how well a person's immune system recognizes the hemagglutinin, the scientists compared the 2009 hemagglutinin protein with the hemagglutinin from all known human H1N1 strains between 1918 and 1957, and representative strains since 1977. The researchers found that while much of the hemagglutinin three-dimensional structure had been maintained among the different viruses, the amino acids (protein building blocks) on the viral surface were substantially different in the 2009 virus from seasonal strains. This could enable the virus to initially evade detection by the immune system.
Notably, the team also found that one area of the hemagglutinin, called antigenic site Sa, was highly similar between the 2009 and the 1918 viruses. The similarity of the Sa site for the two viruses suggested that some individuals might be able to mount an immune response that could neutralize either virus.
"Parts of the 2009 virus are remarkably similar to human H1N1 viruses circulating in the early 20th century," says Scripps Research professor Ian Wilson, the senior author of the study. "Our findings provide strong evidence that exposure to earlier viruses has helped to provide some people with immunity to the recent influenza pandemic."
At the same time as this discovery, another flu project in Wilson's lab was working to determine the structure of the antibody 2D1 that neutralized the 1918 influenza virus. The antibody had been isolated from a survivor of the 1918 Spanish flu. Researchers at Vanderbilt University, who have been collaborating with Wilson's lab, recently published an article in the Journal of Virology that showed mice challenged with the 2009 virus are protected by the administration of the antibody against the 1918 virus. Wilson's current study shows that prior exposure to viruses that were around decades ago can provide some protection against infection against a newly emerging pandemic.
The information should be useful for scientists and public health officials as they respond to current and future pandemics, Wilson says.
"It brings into question how we deal with vaccinations," Wilson says. It suggests that we should think differently about vaccination strategies for viruses that disappear for a while, but are resident in pigs and wild birds, because they can drift off and wait long enough for people to lose their heteroimmunity to the virus that started the whole pandemic strain."
Other authors of the paper, "Structural basis of pre-existing immunity to the 2009 H1N1 pandemic influenza virus," include Rui Xu, a research associate in Wilson's lab, who was first author of the paper with graduate student Damian Ekiert, also of the Wilson lab; Jens C. Krause and James E. Crowe Jr. of Vanderbilt University Medical Center; and Rong Hai of the Mount Sinai School of Medicine.
The work was supported by the National Institutes of Health (NIH), the Skaggs Institute for Chemical Biology, and predoctoral fellowships from the Achievement Rewards for College Scientists Foundation and the NIH Molecular Evolution Training Program. X-ray diffraction datasets were collected at the Stanford Synchrotron Radiation Lightsource and the Advanced Photon Source, which are supported by NIH and the U.S. Department of Energy.
This image, from the Scripps Research Wilson lab, shows part of the 1918 Spanish flu virus in complex with an antibody that also neutralizes the 2009 "swine flu" virus. The antibody 2D1 Fab is depicted as red and yellow ribbons. The hemagglutinin on the flu virus is depicted as a solid surface. One of the three hemagglutinin subunits is highlighted in blue and cyan. The Sa site—the region conserved between the 1918 and swine flu viruses and targeted by the 2D1 antibody—is highlighted in magenta.
