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ORIGINAL RESEARCH article

Front. Immunol.
Sec. Cytokines and Soluble Mediators in Immunity
Volume 15 - 2024 | doi: 10.3389/fimmu.2024.1444643

SARS-CoV-2 spike protein induces the cytokine release syndrome by stimulating T cells to produce more IL-2

Provisionally accepted
Chao Niu Chao Niu 1Tingting Liang Tingting Liang 1Yongchong Chen Yongchong Chen 1*Shan Zhu Shan Zhu 2Lei Zhou Lei Zhou 1Naifei Chen Naifei Chen 1Lei Qian Lei Qian 1*Yufeng Wang Yufeng Wang 1Min Li Min Li 1*Xin Zhou Xin Zhou 1*Jiuwei Cui Jiuwei Cui 1*
  • 1 Cancer Center, The First Hospital of Jilin University, Changchun, China
  • 2 Institute of Translational Medicine, The First Hospital of Jilin University, Changchun, China

The final, formatted version of the article will be published soon.

    Cytokine release syndrome (CRS) is one of the leading causes of mortality in COVID-19 patients caused by the SARS-CoV-2 coronavirus. However, the mechanism of CRS induced by SARS-CoV-2 is vague. This study shows that dendritic cells loaded with spike protein of SARS-CoV-2 stimulate T cells to release much more IL-2, which subsequently cooperates with spike protein to facilitate peripheral blood mononuclear cells to release IL-1β, IL-6, and IL-8. These effects are achieved via IL-2 stimulation of NK cells to release TNF-α and IFN-γ, as well as T cells to release IFN-γ. Mechanistically, IFN-γ and TNF-α enhance the transcription of CD40, and the interaction of CD40 and its ligand stabilizes the membrane expression of TLR4 which serves as a receptor of spike protein on the surface of monocytes. As a result, there is a constant interaction between spike protein and TLR4, leading to continuous activation of NF-κB. Furthermore, TNF-α also activates NF-κB signaling in monocytes, which further cooperates with IFN-γ and spike protein to modulate NF-κB-dependent transcription of CRS-related inflammatory cytokines. Targeting TNF-α/IFN-γ in combination with TLR4 may represent a promising therapeutic approach for alleviating CRS in individuals with COVID-19.

    Keywords: SARS-CoV-2, Spike protein, monocyte, cytokine release syndrome, NF-κB, CD40

    Received: 06 Jun 2024; Accepted: 13 Aug 2024.

    Copyright: © 2024 Niu, Liang, Chen, Zhu, Zhou, Chen, Qian, Wang, Li, Zhou and Cui. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence:
    Yongchong Chen, Cancer Center, The First Hospital of Jilin University, Changchun, China
    Lei Qian, Cancer Center, The First Hospital of Jilin University, Changchun, China
    Min Li, Cancer Center, The First Hospital of Jilin University, Changchun, China
    Xin Zhou, Cancer Center, The First Hospital of Jilin University, Changchun, China
    Jiuwei Cui, Cancer Center, The First Hospital of Jilin University, Changchun, China

    Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.