Exposure to 1918 influenza virus activates memory B-cells

4th March 2013

Recent research has revealed that infection and natural exposure to the 1918 influenza virus made survivors immune to the disease for the remaining of their lives. Antibodies produced by cells isolated from these survivors served as an effective therapy to protect mice from the highly lethal 1918 infection. The study entitled "Neutralizing antibodies derived from the B cells of 1918 influenza pandemic survivors," was published in the journal Nature. Dr. Chris Basler and his colleagues at Mount Sinai School of Medicine's Department of Microbiology contributed to the research findings. Scientist Live spoke with Dr. Basler about his findings.

Can you briefly discuss the effects of the 1918 influenza pandemic and why it was so devastating?

The big question is: why did it kill so many people worldwide? The simple answer is we do not really know. The fact is that now that we have been able to reconstruct the virus in the lab and test it in several animal models. In each case the virus has displayed an unusual degree of virulence. We are beginning to understand why this may be the case. There is some evidence that the virus over-activates the immune response and the hyper-activation of this response may account for the severity of disease. At this point, however, I would say that this is more a hypothesis than a definitive answer.

Another thing that we have begun to do is to define the gene segments of the virus need for high virulence in mice. the virus has eight different sequences encoding eleven different proteins, and we can implicate three or four of these proteins as being important for high virulence phenotype. But we don't at this point really know the exact mechanism that makes the 1918 virus so deadly.

Can you provide an overview of the study you participated in and what you discovered?

The genesis of the study goes back to the public response we received to a paper that described the reconstruction of the 1918 virus. One thing that happened was we started receiving calls and emails from people saying that they had the flu in 1918 as young children or that they knew members of their family had been infected or died of the flu. Many actually offered to contribute to future studies of the virus. It was in interesting idea. What could you do if you had blood from people who had been exposed to the 1918 flu virus? Independently our clinical collaborator Dr. Eric Altschuler had come up with the same idea and it was: Could you obtain blood from these individuals, could you isolate cells from the blood that would make antibodies for 1918 virus and could you use those to characterize the memory immune response? The other side of that question was: can you use antibodies produced in these people as potential therapeutic against the virus? To put this all together, we needed someone who had real expertise in human immunology so we turned to Dr. James Crowe at Vanderbilt University. Then the experimental plan is very straight forward. Dr. Altschuler obtained blood from people born 1915 or earlier. We at Mt. Sinai demonstrated the presence of antibodies. Then the cells were transported to Vanderbilt University where Dr. Crowe was able to isolate memory B-cells which would make antibodies. These then used to isolate the rare B-cells that make antibodies against the 1918 flu. Then we were able to show that the antibodies specifically bind to the 1918 virus and to haemagglutinin protein in particular.

Did your findings fulfill expectations? Surprises?

We knew already, based on previous studies, that people who had been alive in 1918 and who were still alive today would have antibodies against the virus. What was surprising and technically challenging was that we could isolate memory B-cells that appear to be very specific to the 1918 virus which suggests that they were derived from initial exposure to the virus and that B-cells. It's remarkable that these cells were still present in the blood and could be isolated.

The other striking thing about the antibodies we isolated is that they are very potent. They bind to the hemagglutinin proteins with high affinity.

Can the B-Cells be used in vaccine development?

For the most part, the antibodies we isolated are very specific to the 1918 virus. So they would neutralize that and another old influenza virus called Swine 30 virus. Other later human influenza viruses of the H1N1 type weren't recognized by 4 out of 5 antibodies we characterized in detail. One of the antibodies we do have reacts with the 1918 and selectively with some other later viruses. This ability to cross-neutralize different fu viruses is interesting and we are trying to understand how that happens, what this antibody is actually recognizing. Understanding this and other cross-reactive antibodies might suggest ways to make flu vaccines more bradly protective.

(Reporting by Marc Landas)





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