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New insights into how influenza evades human immunity

Influenza's ability to evade the human immune system has long baffled research. Image credit:

Influenza’s ability to evade the human immune system necessitates annual flu shots for millions. Image credit: TaTae THAILAND

Some viruses can only infect people once—measles for example. But other viruses, notably influenza, are capable of infecting repeatedly. Scientists have long puzzled over how the flu virus evades human immunity. Recent work in eLife clarifies exactly how the virus gets the upper hand.

Previous studies have found that a single mutation to the hemagglutinin (HA) protein on the outside of the virus can help it evade individual monoclonal antibodies, which bind to one specific region on the virus protein. But researchers didn’t fully understand how viruses evaded the many different antibodies that make up humans’ polyclonal immunity. The antibodies were thought to bind to many different regions of the virus, making it hard for the virus to escape. “It didn’t seem likely that a single mutation could escape them all,” says eLife paper coauthor Jesse Bloom, a biochemist at the Fred Hutchinson Cancer Research Center in Seattle, WA.

To uncover the virus’ escape route, Juhye Lee, a former PhD student of Bloom’s, designed a means of examining which mutations help the viruses overcome immunity and infect cells. Lee used polymerase chain reaction (PCR) to make approximately 10,000 different mutations to the amino acid building blocks of the HA protein in a strain of the H3N2 virus that was isolated from a human in 2009. The mutant viruses were exposed to different concentrations of antibody-rich blood serum of four individuals ranging in age from 65 years to 21 years. They then infected canine kidney cells with the viruses-antibody mixtures. The team used high-throughput sequencing to determine which mutant viruses were able to replicate in the presence of serum antibodies.

While just a single mutation enabled the virus to escape the antibodies, the site of the escape mutation varied among most of the individual serums. In the serum of subjects aged 65- and 21-years, viruses with a mutation at site F193D on the HA protein could replicate. In the serum of the 64-year-old, viruses with a mutation at site F159G were able to replicate. In all three of these serums, the single mutations reduced immunity by ten-fold, meaning 10 times more antibodies were needed to stop the virus from infecting cells compared to that required by the original non-mutated virus. In a subject aged 53-years, a single mutation at site L157D reduced immunity by five times.

The findings show that human immunity is focused and may come from just one or a few antibodies that target a specific region of the virus protein. The work also demonstrates that one mutation is capable of helping the virus evade antibodies in one person but not in another, explains Bloom. “Despite the fact that our immune system can potentially make antibodies that target all over the viral protein, the results show that human immunity is instead very focused on just one part of the protein,” he says. “Mutations that are strongly selected by one person’s serum often aren’t selected by another person’s serum.”

Sarah Cobey, a researcher at the University of Chicago who studies the evolution of pathogens and their hosts’ immunity, notes that previous findings have suggested that human immunity is narrowly targeted towards specific sites. But she notes that this study “shows beautifully and clearly how narrow this targeting is.” Cobey adds that the study clearly demonstrates “how heterogeneous immune pressure can select for different mutations in influenza viruses.”

This variation in the ability of mutations to help viruses escape immunity could boil down to the variety of histories of flu strain infection among individuals. To see if the variation persists, the team is now repeating their experiments with the blood serum of young children who’ve had a single influenza infection. He hopes the findings from both studies can help researchers to develop better targeted vaccinations against influenza.

Categories: Immunology | Infectious disease | Journal Club | Medical Sciences and tagged | | | |
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