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J Virol. 2019 Feb 6. pii: JVI.00169-19. doi: 10.1128/JVI.00169-19. [Epub ahead of print]

Broad hemagglutinin-specific memory B cell expansion by seasonal influenza virus infection reflects early-life imprinting and adaptation to the infecting virus.

Author information

1
Division of Infectious Diseases, Department of Pediatrics, University of Rochester Medical Center, Rochester, New York, USA.
2
David H. Smith Center for Vaccine Biology and Immunology, Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, New York, USA.
3
Division of Nephrology, Department of Medicine, University of Rochester Medical Center, Rochester, New York, USA.
4
Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, Maryland, USA.
5
Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, New York, USA.
6
Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, Georgia, USA.
7
Department of Microbiology, Icahn School of Medicine at Mt. Sinai, New York, New York, USA.
8
Department of Biostatistics and Computational Biology, University of Rochester Medical Center, Rochester, New York, USA.
9
Department of Medicine, University of Rochester Medical Center, Rochester, New York, USA.
10
David H. Smith Center for Vaccine Biology and Immunology, Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, New York, USA mark_sangster@urmc.rochester.edu.

Abstract

Memory B cells (MBCs) are key determinants of the B cell response to influenza virus infection and vaccination, but the effect of different forms of influenza antigen exposure on MBC populations has received little attention. We analyzed peripheral blood mononuclear cells and plasma collected following human H3N2 influenza infection to investigate the relationship between hemagglutinin-specific antibody production and changes in the size and character of hemagglutinin-reactive MBC populations. Infection produced increased concentrations of plasma IgG reactive to the H3 head of the infecting virus, to the conserved stalk, and to a broad chronological range of H3s consistent with original antigenic sin responses. H3-reactive IgG MBC expansion after infection included reactivity to head and stalk domains. Notably, expansion of H3 head-reactive MBC populations was particularly broad and reflected original antigenic sin patterns of IgG production. Findings also suggest that early-life H3N2 infection "imprints" for strong H3 stalk-specific MBC expansion. Despite the breadth of MBC expansion, the MBC response included an increase in affinity for the H3 head of the infecting virus. Overall, our findings indicate that H3-reactive MBC expansion following H3N2 infection is consistent with maintenance of response patterns established early in life, but nevertheless includes MBC adaptation to the infecting virus.IMPORTANCE Rapid and vigorous virus-specific antibody responses to influenza virus infection and vaccination result from activation of preexisting virus-specific memory B cells (MBCs). Understanding the effects of different forms of influenza virus exposure on MBC populations is therefore an important guide to the development of effective immunization strategies. We demonstrate that exposure to the influenza hemagglutinin via natural infection enhances broad protection through expansion of hemagglutinin-reactive MBC populations that recognize head and stalk regions of the molecule. Notably, we show that hemagglutinin-reactive MBC expansion reflects imprinting by early-life infection and that this might apply to stalk-reactive, as well as to head-reactive, MBCs. Our findings provide experimental support for the role of MBCs in maintaining imprinting effects and suggest a mechanism by which imprinting might confer heterosubtypic protection against avian influenza viruses. It will be important to compare our findings to the situation after influenza vaccination.

PMID:
30728266
DOI:
10.1128/JVI.00169-19

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