High-dimensional single-cell phenotyping unveils persistent differences in immune cell profiles between severe and moderate seasonal influenza

Frontiers in Immunology, vol. 16, pp. 1576861

Abstract

Background Influenza viruses with pandemic potential and possible burden of post-viral sequelae are a global concern. To prepare for future pandemics and the development of improved vaccines, it is vital to identify the immunological changes underlying influenza disease severity. Methods We combined unsupervised high-dimensional single-cell mass cytometry with gene expression analyses, plasma CXCL13 measurements, and antigen-specific immune cell assays to characterize the immune profiles of hospitalized patients with severe and moderate seasonal influenza disease during active infection and at 6-month follow-up. We used age-matched healthy donors as controls. Results Severe disease was associated with a distinct immune profile, including lower frequencies of ICOS+ mucosal-associated invariant T (MAIT) cells, and CXCR5+ memory B and CD4+CXCR5+CD95+ICOS+ and CD8+CXCR3+CD95+PD-1+TIGIT+ memory T cells, as well as lower CD4 gene expression. Higher frequencies of CD16+CD161+ NK cells, CD169+ monocytes, CD123+/− dendritic cells, and CD38high plasma cells and high CXCL13 plasma levels were also associated with severe disease. Alterations in immune cell subpopulations persisted at convalescence for the severely ill patients only. Conclusions Our results indicated a reduction in regulatory MAIT cells and memory T and B cells and an increase in the inhibitory subpopulations of monocytes and NK cells in severe influenza that persisted at convalescence. These immune cell alterations were associated with higher age and the presence of several underlying conditions that may contribute to frailty. This study illustrates the power and sensitivity of high-dimensional single-cell analyses in identifying potential cellular biomarkers for disease severity after influenza infection.

Authors 17

1. Johanna Bodin corresponding

   Norwegian Institute of Public Health

   Affiliation as printed

   Section of Immunology, Department of Method Development and Analytics, Norwegian Institute of Public Health, Oslo, Norway

   Section of Immunology, Department of Method Development and Analytics, Norwegian Institute of Public Health, Oslo, Norway

2. Gro Tunheim

   Norwegian Institute of Public Health

   Affiliation as printed

   Section of Immunology, Department of Method Development and Analytics, Norwegian Institute of Public Health, Oslo, Norway

   Section of Immunology, Department of Method Development and Analytics, Norwegian Institute of Public Health, Oslo, Norway

3. Anja Bråthen Kristoffersen

   Norwegian Institute of Public Health

   Affiliation as printed

   Section of Immunology, Department of Method Development and Analytics, Norwegian Institute of Public Health, Oslo, Norway

   Section of Immunology, Department of Method Development and Analytics, Norwegian Institute of Public Health, Oslo, Norway

4. Tove Karin Herstad

   Norwegian Institute of Public Health

   Affiliation as printed

   Section of Immunology, Department of Method Development and Analytics, Norwegian Institute of Public Health, Oslo, Norway

   Section of Immunology, Department of Method Development and Analytics, Norwegian Institute of Public Health, Oslo, Norway

5. Eleonora Vianello Aachen Department of Infectious Diseases

   Leiden University Medical Center

   Affiliation as printed

   Department of Infectious Diseases, Leiden University Medical Center, Leiden, Netherlands

   Department of Infectious Diseases, Leiden University Medical Center, Leiden, Netherlands

6. Mariëlle C. Haks Aachen Department of Infectious Diseases

   Leiden University Medical Center

   Affiliation as printed

   Department of Infectious Diseases, Leiden University Medical Center, Leiden, Netherlands

   Department of Infectious Diseases, Leiden University Medical Center, Leiden, Netherlands

7. Suzanne van Veen Aachen Department of Infectious Diseases

   Leiden University Medical Center

   Affiliation as printed

   Department of Infectious Diseases, Leiden University Medical Center, Leiden, Netherlands

   Department of Infectious Diseases, Leiden University Medical Center, Leiden, Netherlands

8. Torgun Wæhre

   Oslo University Hospital

   Affiliation as printed

   Department of Infectious Diseases, Oslo University Hospital, Oslo, Norway

   Department of Infectious Diseases, Oslo University Hospital, Oslo, Norway

9. Anne‐Marte Bakken Kran

   Oslo University Hospital · Norwegian Institute of Public Health

   Affiliation as printed

   Department of Microbiology, Oslo University Hospital, Oslo, Norway

   Division of Infection Control, Department of Infectious Disease Registries, Norwegian Institute of Public Health, Oslo, Norway

   Department of Microbiology, Oslo University Hospital, Oslo, Norway

   Division of Infection Control, Department of Infectious Disease Registries, Norwegian Institute of Public Health, Oslo, Norway

10. Sarah Larteley Lartey

    University of Bergen

    Affiliation as printed

    Influenza Centre, Department of Clinical Science, University of Bergen, Bergen, Norway

    Influenza Centre, Department of Clinical Science, University of Bergen, Bergen, Norway

11. Fan Zhou

    University of Bergen

    Affiliation as printed

    Influenza Centre, Department of Clinical Science, University of Bergen, Bergen, Norway

    Influenza Centre, Department of Clinical Science, University of Bergen, Bergen, Norway

12. Rebecca Jane Cox corresponding

    Haukeland University Hospital · University of Bergen

    Affiliation as printed

    Department of Microbiology, Haukeland University Hospital, Bergen, Norway

    Influenza Centre, Department of Clinical Science, University of Bergen, Bergen, Norway

    Department of Microbiology, Haukeland University Hospital, Bergen, Norway

    Influenza Centre, Department of Clinical Science, University of Bergen, Bergen, Norway

13. Tom H. M. Ottenhoff Aachen Department of Infectious Diseases

    Leiden University Medical Center

    Affiliation as printed

    Department of Infectious Diseases, Leiden University Medical Center, Leiden, Netherlands

    Department of Infectious Diseases, Leiden University Medical Center, Leiden, Netherlands

14. Anne Ma Dyrhol‐Riise

    Oslo University Hospital · University of Oslo

    Affiliation as printed

    Department of Infectious Diseases, Oslo University Hospital, Oslo, Norway

    Institute of Clinical Medicine, University of Oslo, Oslo, Norway

    Department of Infectious Diseases, Oslo University Hospital, Oslo, Norway

    Institute of Clinical Medicine, University of Oslo, Oslo, Norway

15. Unni Cecilie Nygaard

    Norwegian Institute of Public Health

    Affiliation as printed

    Section of Immunology, Department of Method Development and Analytics, Norwegian Institute of Public Health, Oslo, Norway

    Section of Immunology, Department of Method Development and Analytics, Norwegian Institute of Public Health, Oslo, Norway

16. Fredrik Oftung

    Norwegian Institute of Public Health

    Affiliation as printed

    Section of Immunology, Department of Method Development and Analytics, Norwegian Institute of Public Health, Oslo, Norway

    Section of Immunology, Department of Method Development and Analytics, Norwegian Institute of Public Health, Oslo, Norway

17. Siri Mjaaland corresponding

    Norwegian Institute of Public Health

    Affiliation as printed

    Section of Immunology, Department of Method Development and Analytics, Norwegian Institute of Public Health, Oslo, Norway

    Section of Immunology, Department of Method Development and Analytics, Norwegian Institute of Public Health, Oslo, Norway