Say you’re blindfolded and you’re given some kind of ball to identify. You turn it over in your hands. It’s relatively small. It’s very hard. It has pronounced seams with big stitching. You know it’s a baseball…providing, of course, that you’ve handled baseballs before. So it is with your immune system facing a virus. By analogy the immune system probes the surface of the virus looking for a molecular configuration it has seen before. If it recognizes the virus, it starts to produce anti-bodies. If the virus isn’t recognized – that’s where real trouble begins. Pandemics are made by viruses that all or most immune systems do not recognize.
An international team of researchers, working through the Scripps Research Institute, Wilson Lab have been studying the H1N1 (‘swine flu’) virus, looking for connections between this virus and those of previous flu pandemics. What they found, a similarity between the surface of H1N1 (the hemagglutinin layer) and that of the Spanish flu virus of 1908, provides a means for analyzing the effects of the H1N1 outbreak and why it affected relatively few elderly.
Almost from the beginning of the H1N1 outbreak in 2009, the research team began to examine the structure of the virus. Rather than try to analyze the entire organism, they focused on the outer layer – specifically the hemagglutinin – because that’s what the human immune system reacts to. Hemagglutinin is a protein. It has a specific shape, or configuration, and is found all over the surface of the virus. It’s also very small – a few microns in size. To see it, a high-powered x-ray crystallography machine was used on crystals made from the viral protein. X-rays passing through the crystal diffract (bend or spread out at angles) in a pattern that can be detected and interpreted. This gave the researchers the identifying shape of the hemagglutinin molecule.
Next came the slog work: comparing this protein’s molecular shape with those in H1N1 flu viruses of the past, particularly from the pandemics of 1908, 1957, and 1968. They found that the three-dimensional structure of hemagglutinin remained fairly constant over the years. However the amino acids (the building blocks of this and all other proteins) were different in the 2009 virus from those of seasonal strains of the flu. The difference in the composition of the hemagglutinin protein could account for why this strain was able to go undetected by the immune system.
They also discovered that one area of the hemagglutinin, labeled antigenic site Sa (antigenic meaning a spot that triggers recognition by the immune system) was very similar to the same site on the 1918 virus. This suggested that there might be some elderly people who were living around that time who may have an immune system that indeed recognizes the H1N1 strain of today and is able to mount a defense against it. To confirm this, the team encountered a piece of good luck…
“As more information became available, the 1918 antibody suddenly became relevant to the swine flu study,” said Ekiert [graduate student at Wilson Lab].
Could the particular antibody that Ekiert was working with, called 2D1, not only be effective against the 1918 virus, but also act against the 2009 swine flu?
A study recently published in the Journal of Virology with researchers at Vanderbilt University, who are collaborators on this present work, showed that, indeed, mice challenged with the 2009 virus are protected by the administration of the antibody against the 1918 virus. The current Science Express study provides the structure of the 2D1 antibody in complex with the 1918 virus and addresses how this protection occurs.
“There is a huge divergence among different influenza viruses,” said Ekiert, “so that exposure to one won’t confer protection against another. However, this study shows that prior exposure to viruses that were around decades ago can provide some protection against infection against a newly emerging pandemic.”