The human immune system protects the body from repeat attacks of the same pathogen by remembering past infections. However, viral antigenic evolution reduces the effectiveness of this immune memory against future strains of viral infections. As a result, a typical person comes down with the flu every five to seven years on average. The rapid evolution of flu viruses makes them less recognizable to the immune system, and poses a challenge to protecting the body from infection.
The immune system recognizes flu viruses by producing antibodies, which can bind to the virus and prevent it from infecting cells. Many of these antibodies bind to a protein on the surface of the virus called hemagglutinin (HA). However each anti-flu antibody recognizes only a small region of the protein. Therefore, a mutation that changes the part of hemagglutinin recognized by a particular antibody will allow the virus to escape recognition by that single antibody clone, but not other clones. Consequently, a substantial number of mutations are required for the virus to escape the large number and variety of antibodies generated by a typical human immune system. So how do flu viruses keep evading human immunity?
Dr. Jesse Bloom and members of his laboratory in the Basic Sciences division, teamed up with other investigators to answer this question. Led by Dr. Juhye Lee, a former graduate student in the Bloom lab, the authors made all possible individual mutations to the hemagglutinin protein of a human flu virus and studied how these mutations affected neutralization of H3N2 influenza virus by polyclonal human sera. The authors showed how different single mutations help influenza virus escape the immunity of different members of the human population, suggesting that person-to-person variation may play an important role in shaping viral evolution and disease susceptibility. These results were published in a recent issue of the journal eLife.
To do this, the authors generated libraries of mutant viruses carrying all mutations compatible with viral growth to HA from the A/Perth/16/2009 viral strain, which was the H3N2 component of the influenza vaccine from 2010 to 2012. Four monoclonal antibodies from humans who received the 2010-2011 trivalent influenza vaccine were used to validate the mutational antigenic profiling. A pool of these viruses was then exposed to the full mix of antibodies present in a panel of human sera and subsequently infected into cells. To ascertain which mutations helped the virus survive contact with the antibodies, viral RNA from infected cells were deep sequenced to measure the frequency of each mutation.
The authors reported that for most human serum samples, a single mutation was sufficient to allow the virus to escape the majority of an individual’s anti-flu antibodies. This suggests that the immune response to flu is so focused on a small region of hemagglutinin that a mutation in this region can enable the virus to take a huge step towards evading immune detection.
Strikingly, the authors found that the targets of serum selection varied widely between different individuals. Viral mutations that greatly reduced neutralization by one individual’s serum sometimes had no effect for another individual’s serum, which is instead affected by different mutations.
There is evidence that exposure history can influence human immunity to influenza; differences in exposure history may be a potential explanation to the person-to-person variation observed in this study. Singly infected ferrets have been used as the primary tool for characterizing viral antigenicity. As such, the authors also performed mutational antigenic profiling using sera from five ferrets from different laboratories and viral strains to sample across factors that might affect serum specificity. In contrast to the person-to-person variation of data from human sera, immune selections were similar for all post-infection ferret sera, illuminating the potential influence of exposure history.
Since there are several related flu virus strains that can infect humans, these results suggest how individuals can be susceptible to different strains of the virus. Understanding how flu viruses escape immune detection in different individuals can help identify which version of the virus different people are more susceptible to, and perhaps eventually better predict how the virus will evolve and spread.
Lee JM, Equia R, Zost SJ, Choudhary S, Wilson PC, Bedford T, Stevens-Ayers T, Boeckh M, Hurt AC, Lakdawala SS, Hensley SE, Bloom JD. 2019. Mapping person-to-person variation in viral mutations that escape polyclonal serum targeting influenza hemagglutinin. eLife Aug 27; 8 pii: e49324.
This work was supported by the National Institutes of Health, Burroughs Wellcome Fund, Pew Charitable Trusts and the Howard Hughes Medical Institute.