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bioRxiv · 10.1101/2023.11.01.565098

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

Niu, C.·Liang, T.·Chen, Y.·Zhu, S.·Zhou, L.·Chen, N.·Qian, L.·Wang, Y.·Li, M.·Zhou, X.·Cui, J.
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Abstract

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-1{beta}, IL-6, and IL-8. These effects are achieved via IL-2 stimulation of NK cells to release TNF- and IFN-{gamma}, as well as T cells to release IFN-{gamma}. Mechanistically, IFN-{gamma} and TNF- 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-{kappa}B. Furthermore, TNF- also activates NF-{kappa}B signaling in monocytes, which further cooperates with IFN-{gamma} and spike protein to modulate NF-{kappa}B-dependent transcription of CRS-related inflammatory cytokines. Targeting TNF-/IFN-{gamma} in combination with TLR4 may represent a promising therapeutic approach for alleviating CRS in individuals with COVID-19.

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Niu, C., Liang, T., Chen, Y., Zhu, S., Zhou, L., Chen, N., Qian, L., Wang, Y., Li, M., Zhou, X., Cui, J.. 2023-11-01. SARS-CoV-2 spike protein induces the cytokine release syndrome by stimulating T cells to produce more IL-2. https://doi.org/10.1101/2023.11.01.565098

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