1. Immunology and Inflammation
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SARS-CoV-2 spike protein induces inflammation via TLR2-dependent activation of the NF-kB pathway

  1. Shahanshah Khan
  2. Mahnoush Shafiei
  3. Christopher Longoria
  4. John W Schoggins
  5. Rashmin Savani
  6. Hasan Zaki  Is a corresponding author
  1. The University of Texas Southwestern Medical Center, United States
Research Article
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Cite this article as: eLife 2021;10:e68563 doi: 10.7554/eLife.68563

Abstract

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.

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There is no clinical data and large data set in this paper. The raw data for all graphs presented in this paper are submitted in the source data section.

Article and author information

Author details

  1. Shahanshah Khan

    Department of Pathology, The University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3052-932X
  2. Mahnoush Shafiei

    Department of Pathology, The University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    No competing interests declared.
  3. Christopher Longoria

    Department of Pediatrics, The University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    No competing interests declared.
  4. John W Schoggins

    Department of Microbiology, The University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    John W Schoggins, Reviewing editor, eLife.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7944-6800
  5. Rashmin Savani

    Department of Pediatrics, The University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    No competing interests declared.
  6. Hasan Zaki

    Department of Pathology, The University of Texas Southwestern Medical Center, Dallas, United States
    For correspondence
    hasan.zaki@utsouthwestern.edu
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9002-5399

Funding

Cancer Prevention and Research Institute of Texas (RP200184)

  • Hasan Zaki

National Institute of Diabetes and Digestive and Kidney Diseases (R01DK125352)

  • Hasan Zaki

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 studies were approved by the Institutional Animal Care and Use Committee (IACUC) and were conducted in accordance with the IACUC guidelines and the National Institutes of Health Guide for the Care and Use of Laboratory Animals. The IACUC permit number is 2016-101683

Reviewing Editor

  1. Joshua T Schiffer, Fred Hutchinson Cancer Research Center, United States

Publication history

  1. Received: March 19, 2021
  2. Accepted: December 1, 2021
  3. Accepted Manuscript published: December 6, 2021 (version 1)
  4. Version of Record published: December 24, 2021 (version 2)

Copyright

© 2021, Khan 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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