SKAP2 is required for defense against K. pneumoniae infection and neutrophil respiratory burst

  1. Giang T Nguyen
  2. Lamyaa Shaban
  3. Matthias Mack
  4. Kenneth D Swanson
  5. Stephen C Bunnell
  6. David B Sykes
  7. Joan Mecsas  Is a corresponding author
  1. Tufts Graduate School of Biomedical Sciences, United States
  2. University Hospital Regensburg, Germany
  3. Beth Israel Deaconess Medical Center, United States
  4. Tufts University School of Medicine, United States
  5. Massachusetts General Hospital, United States

Abstract

Klebsiella pneumoniae is a respiratory, blood, liver, and bladder pathogen of significant clinical concern. We show that the adaptor protein, SKAP2, is required for protection against K. pneumoniae (ATCC 43816) pulmonary infections. Skap2-/- mice had 100-fold higher bacterial burden when compared to wild-type and burden was controlled by SKAP2 expression in innate immune cells. Skap2-/- neutrophils and monocytes were present in infected lungs, and the neutrophils degranulated normally in response to K. pneumoniae infection in mice; however, K. pneumoniae-stimulated reactive oxygen species (ROS) production in vitro was abolished. K. pneumoniae-induced neutrophil ROS response required the activity of SFKs, Syk, Btk, PLCg2, and PKCs. The loss of SKAP2 significantly hindered the K. pneumoniae-induced phosphorylation of SFKs, Syk, and Pyk2 implicating SKAP2 as proximal to their activation in pathogen-signaling pathways. In conclusion, SKAP2-dependent signaling in neutrophils is essential for K. pneumoniae-activated ROS production and for promoting bacterial clearance during infection.

Data availability

All data generated and analyzed during this study are included in the manuscript and supporting files.

Article and author information

Author details

  1. Giang T Nguyen

    Graduate Program in Immunology, Tufts Graduate School of Biomedical Sciences, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8967-3396
  2. Lamyaa Shaban

    Graduate Program in Molecular Microbiology, Tufts Graduate School of Biomedical Sciences, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Matthias Mack

    Department of Internal Medicine II, University Hospital Regensburg, Regensburg, Germany
    Competing interests
    The authors declare that no competing interests exist.
  4. Kenneth D Swanson

    Brain Tumor Center and Neuro-Oncology Unit, Beth Israel Deaconess Medical Center, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Stephen C Bunnell

    Department of Immunology, Tufts University School of Medicine, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6887-0828
  6. David B Sykes

    Center for Regenerative Medicine, Massachusetts General Hospital, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Joan Mecsas

    Molecular Biology and Microbiology, Tufts University School of Medicine, Boston, United States
    For correspondence
    joan.mecsas@tufts.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9455-6672

Funding

National Institutes of Health (R01 AI113166)

  • Joan Mecsas

National Institutes of Health (4T32AI007422)

  • Lamyaa Shaban

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 animal experimental procedures followed NIH guidelines. All mice were handled in accordance with protocols (B2018-10) approved by the Institutional Animal Care and Use Committee (IACUC) of Tufts University.

Reviewing Editor

  1. Christina L Stallings, Washington University School of Medicine, United States

Publication history

  1. Received: March 5, 2020
  2. Accepted: April 29, 2020
  3. Accepted Manuscript published: April 30, 2020 (version 1)
  4. Version of Record published: May 26, 2020 (version 2)

Copyright

© 2020, Nguyen 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. Giang T Nguyen
  2. Lamyaa Shaban
  3. Matthias Mack
  4. Kenneth D Swanson
  5. Stephen C Bunnell
  6. David B Sykes
  7. Joan Mecsas
(2020)
SKAP2 is required for defense against K. pneumoniae infection and neutrophil respiratory burst
eLife 9:e56656.
https://doi.org/10.7554/eLife.56656

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