HIF1α is required for NK cell metabolic adaptation during virus infection

  1. Francisco Victorino  Is a corresponding author
  2. Tarin Bigley
  3. Eugene Park
  4. Cong-Hui Yao
  5. Jeanne Benoit
  6. Liping Yang
  7. Sytse J Piersma
  8. Elvin J Lauron
  9. Rebecca M Davidson
  10. Gary Patti
  11. Wayne M Yokoyama  Is a corresponding author
  1. Washington University School of Medicine, United States
  2. Washington University, United States
  3. National Jewish Health, United States
  4. University of Iowa, United States

Abstract

Natural killer (NK) cells are essential for early protection against virus infection, and must metabolically adapt to the energy demands of activation. Here, we found upregulation of the metabolic adaptor hypoxia inducible factor-1α (HIF-1α) is a feature of mouse NK cells during murine cytomegalovirus (MCMV) infection in vivo. HIF-1 α -deficient NK cells failed to control viral load, causing increased morbidity. No defects were found in effector functions of HIF-1α KO NK cells however, their numbers were significantly reduced. Loss of HIF-1 α did not affect NK cell proliferation during in vivo infection and in vitro cytokine stimulation. Instead, we found HIF-1α -deficient NK cells showed increased expression of the pro-apoptotic protein Bim and glucose metabolism was impaired during cytokine stimulation in vitro. Similarly, during MCMV infection HIF-1α -deficient NK cells upregulated Bim and had increased caspase activity. Thus, NK cells require HIF-1α-dependent metabolic functions to repress Bim expression and sustain cell numbers for an optimal virus response.

Data availability

Data generated or analyzed during this study has been deposited to the Dryad Digital Depository, available here: doi:10.5061/dryad.n5tb2rbvm

The following data sets were generated

Article and author information

Author details

  1. Francisco Victorino

    Rheumatology Division, Washington University School of Medicine, St. Louis, United States
    For correspondence
    ramirezvictorino@wustl.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7626-3219
  2. Tarin Bigley

    Rheumatology Division, Washington University School of Medicine, St. Louis, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Eugene Park

    Rheumatology Division, Washington University School of Medicine, St. Louis, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2617-7571
  4. Cong-Hui Yao

    Department of Chemistry, Department of Medicine, Washington University, St. Louis, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Jeanne Benoit

    Department of Biomedical Research, Center for Genes, Environment and Health, National Jewish Health, Denver, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Liping Yang

    Division of Rheumatology, Department of Medicine, Washington University School of Medicine, St Louis, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Sytse J Piersma

    Division of Rheumatology, Department of Medicine, Washington University School of Medicine, St Louis, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5379-3556
  8. Elvin J Lauron

    Rheumatology Division, Washington University School of Medicine, St. Louis, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Rebecca M Davidson

    Department of Biomedical Research, Center for Genes, Environment and Health, National Jewish Health, Denver, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Gary Patti

    FOEDRC Metabolomics Core Facility, University of Iowa, Iowa City, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3748-6193
  11. Wayne M Yokoyama

    Department of Medicine, Washington University School of Medicine, St Louis, United States
    For correspondence
    yokoyama@wustl.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0566-7264

Funding

National Institute of Environmental Health Sciences (R35ES028365)

  • Gary Patti

National Institute of Allergy and Infectious Diseases (R01-AI131680)

  • Wayne M Yokoyama

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols (#20180293) of the University of Washington in St. Louis School of Medicine.

Copyright

© 2021, Victorino et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Francisco Victorino
  2. Tarin Bigley
  3. Eugene Park
  4. Cong-Hui Yao
  5. Jeanne Benoit
  6. Liping Yang
  7. Sytse J Piersma
  8. Elvin J Lauron
  9. Rebecca M Davidson
  10. Gary Patti
  11. Wayne M Yokoyama
(2021)
HIF1α is required for NK cell metabolic adaptation during virus infection
eLife 10:e68484.
https://doi.org/10.7554/eLife.68484

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https://doi.org/10.7554/eLife.68484