1. Immunology and Inflammation
Download icon

IL-21/type I interferon interplay regulates neutrophil-dependent innate immune responses to Staphylococcus aureus

  1. Rosanne Spolski  Is a corresponding author
  2. Erin E West
  3. Peng Li
  4. Sharon Veenbergen
  5. Sunny Yung
  6. Majid Kazemian
  7. Jangsuk Oh
  8. Zu-Xi Yu
  9. Alexandra F Freeman
  10. Stephen M Holland
  11. Philip M Murphy
  12. Warren J Leonard  Is a corresponding author
  1. National Heart, Lung, and Blood Institute, United States
  2. National Institute of Allergy and Infectious Diseases, Netherlands
  3. National Institute of Allergy and Infectious Diseases, United States
Research Article
  • Cited 7
  • Views 1,881
  • Annotations
Cite this article as: eLife 2019;8:e45501 doi: 10.7554/eLife.45501

Abstract

Methicillin-resistant Staphylococcus aureus (MRSA) is a major hospital- and community-acquired pathogen, but the mechanisms underlying host-defense to MRSA remain poorly understood. Here, we investigated the role of IL-21 in this process. When administered intra-tracheally into wild-type mice, IL-21 induced granzymes and augmented clearance of pulmonary MRSA but not when neutrophils were depleted or a granzyme B inhibitor was added. Correspondingly, IL-21 induced MRSA killing by human peripheral blood neutrophils. Unexpectedly, however, basal MRSA clearance was enhanced when IL-21 signaling was blocked, both in Il21r KO mice and in wild-type mice injected with IL-21R-Fc fusion-protein. This correlated with increased type I interferon and an IFN-related gene signature, and indeed anti-IFNAR1 treatment diminished MRSA clearance in these animals. Moreover, we found that IFNb induced granzyme B and promoted MRSA clearance in a granzyme B-dependent fashion. These results reveal an interplay between IL-21 and type-I IFN in the innate immune response to MRSA.

Data availability

All sequencing data in the final manuscript will be deposited in GEO.

The following data sets were generated

Article and author information

Author details

  1. Rosanne Spolski

    Laboratory of Molecular Immunology and the Immunology Center, National Heart, Lung, and Blood Institute, Bethesda, United States
    For correspondence
    spolskir@nhlbi.nih.gov
    Competing interests
    The authors declare that no competing interests exist.
  2. Erin E West

    Laboratory of Molecular Immunology and the Immunology Center, National Heart, Lung, and Blood Institute, Bethesda, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Peng Li

    Laboratory of Molecular Immunology and the Immunology Center, National Heart, Lung, and Blood Institute, Bethesda, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Sharon Veenbergen

    Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases, Bethesda, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
  5. Sunny Yung

    Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases, Bethesda, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Majid Kazemian

    Laboratory of Molecular Immunology and the Immunology Center, National Heart, Lung, and Blood Institute, Bethesda, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7080-8820
  7. Jangsuk Oh

    Laboratory of Molecular Immunology and the Immunology Center, National Heart, Lung, and Blood Institute, Bethesda, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Zu-Xi Yu

    The Pathology Core, National Heart, Lung, and Blood Institute, Bethesda, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Alexandra F Freeman

    Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, Bethesda, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Stephen M Holland

    Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, Bethesda, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Philip M Murphy

    Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases, Bethesda, United States
    Competing interests
    The authors declare that no competing interests exist.
  12. Warren J Leonard

    Laboratory of Molecular Immunology and the Immunology Center, National Heart, Lung, and Blood Institute, Bethesda, United States
    For correspondence
    wjl@helix.nih.gov
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5740-7448

Funding

National Institutes of Health (Division of Intramural Research, NHLBI)

  • Warren J Leonard

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

Ethics

Animal experimentation: Experiments involving animals were performed under protocols (H-0087R4) approved by the National Heart, Lung, and Blood Institute Animal Care and Use Committee and followed National Institutes of Health guidelines for use of animals in intramural research.

Human subjects: Blood samples were obtain from normal donors from the NIH Blood Bank under a waiver from the NIH Office of Human Subjects research. Blood samples were also obtained from AD-HIES patients who had given informed consent under an NIH IRB-approved protocol.

Reviewing Editor

  1. Wayne M Yokoyama, Washington University School of Medicine, United States

Publication history

  1. Received: January 24, 2019
  2. Accepted: April 9, 2019
  3. Accepted Manuscript published: April 10, 2019 (version 1)
  4. Accepted Manuscript updated: April 16, 2019 (version 2)
  5. Version of Record published: May 7, 2019 (version 3)

Copyright

This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.

Metrics

  • 1,881
    Page views
  • 278
    Downloads
  • 7
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Download citations (links to download the citations from this article in formats compatible with various reference manager tools)

Open citations (links to open the citations from this article in various online reference manager services)

Further reading

    1. Genetics and Genomics
    2. Immunology and Inflammation
    Ilana Fox-Fisher et al.
    Research Article Updated

    Blood cell counts often fail to report on immune processes occurring in remote tissues. Here, we use immune cell type-specific methylation patterns in circulating cell-free DNA (cfDNA) for studying human immune cell dynamics. We characterized cfDNA released from specific immune cell types in healthy individuals (N = 242), cross sectionally and longitudinally. Immune cfDNA levels had no individual steady state as opposed to blood cell counts, suggesting that cfDNA concentration reflects adjustment of cell survival to maintain homeostatic cell numbers. We also observed selective elevation of immune-derived cfDNA upon perturbations of immune homeostasis. Following influenza vaccination (N = 92), B-cell-derived cfDNA levels increased prior to elevated B-cell counts and predicted efficacy of antibody production. Patients with eosinophilic esophagitis (N = 21) and B-cell lymphoma (N = 27) showed selective elevation of eosinophil and B-cell cfDNA, respectively, which were undetectable by cell counts in blood. Immune-derived cfDNA provides a novel biomarker for monitoring immune responses to physiological and pathological processes that are not accessible using conventional methods.

    1. Immunology and Inflammation
    Shahanshah Khan et al.
    Research Article

    The pathogenesis of COVID-19 is associated with a hyperinflammatory response; however, the precise mechanism of SARS-CoV-2-induced inflammation is poorly understood. Here we investigated direct inflammatory functions of major structural proteins of SARS-CoV-2. We observed that spike (S) protein potently induced inflammatory cytokines and chemokines including IL-6, IL-1b, TNFa, CXCL1, CXCL2, and CCL2, but not IFNs in human and mouse macrophages. No such inflammatory response was observed in response to membrane (M), envelope (E), and nucleocapsid (N) proteins. When stimulated with extracellular S protein, human and mouse lung epithelial cells also produced inflammatory cytokines and chemokines. Interestingly, epithelial cells expressing S protein intracellularly were non-inflammatory, but elicited an inflammatory response in macrophages when co-cultured. Biochemical studies revealed that S protein triggers inflammation via activation of the NF-kB pathway in a MyD88-dependent manner. Further, such an activation of the NF-kB pathway was abrogated in Tlr2-deficient macrophages. Consistently, administration of S protein induced IL-6, TNF-a, and IL-1b in wild-type, but not Tlr2-deficient mice. Notably, upon recognition of S protein, TLR2 dimerizes with TLR1 or TLR6 to activate the NF-kB pathway. Together these data reveal a mechanism for the cytokine storm during SARS-CoV-2 infection and suggest that TLR2 could be a potential therapeutic target for COVID-19.