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Recombinant SARS-CoV-2 Spike Protein and Its Receptor Binding Domain Stimulate Release of Different Pro-Inflammatory Mediators via Activation of Distinct Receptors on Human Microglia Cells

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Abstract

SARS-CoV-2 infects cells via its spike (S) protein binding to its surface receptor angiotensin converting enzyme 2 (ACE2) on target cells and results in acute symptoms involving especially the lungs known as COVID-19. However, increasing evidence indicates that SARS-CoV-2 infection produces neuroinflammation associated with neurological, neuropsychiatric, and cognitive symptoms persists well past the resolution of the infection, known as post-COVID-19 sequalae or long-COVID. The neuroimmune mechanism(s) involved in long-COVID have not been adequately characterized. In this study, we show that recombinant SARS-CoV-2 full-length S protein stimulates release of pro-inflammatory IL-1b, CXCL8, IL-6, and MMP-9 from cultured human microglia via TLR4 receptor activation. Instead, recombinant receptor-binding domain (RBD) stimulates release of TNF-α, IL-18, and S100B via ACE2 signaling. These results provide evidence that SARS-CoV-2 spike protein contributes to neuroinflammation through different mechanisms that may be involved in CNS pathologies associated with long-COVID.

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Data Availability

The datasets generated during and/or analyzed during the current study are not publicly available but are available from the corresponding author on reasonable request.

Abbreviations

ACE2:

Angiotensin-converting enzyme-2

DAMPS:

Damage-associated molecular patterns

MMP9:

Matrix metalloproteinase 9

RBD:

Receptor-binding domain

S:

Spike protein

TLR:

Toll-like receptor

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Funding

The authors declare that this work was supported by Anonymous Donation to Eirini (Irene) Tsilioni and Theoharis C. Theoharides.

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  1. Laboratory of Molecular Immunopharmacology and Drug Discovery, Department of Immunology, Tufts University School of Medicine, 136 Harrison Avenue, Suite 304, Boston, MA, 02111, USA

    Irene Tsilioni & Theoharis C. Theoharides

  2. Institute of Neuro-Immune Medicine, Nova Southeastern University, Clearwater, FL, 33759, USA

    Theoharis C. Theoharides

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  1. Irene Tsilioni
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All authors contributed to the study conception and design. Material preparation, data collection, and analysis were performed by Eirini (Irene) Tsilioni. The first draft of the manuscript was written by Eirini (Irene) Tsilioni and Theoharis C. Theoharides. All authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

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Supplementary Figure 1

SARS-CoV-2 Spike protein stimulates secretion of proinflammatory mediators from human microglia in a dose-dependent manner. SV40 microglia (1.0 x 105 cells) were stimulated with recombinant SARS-CoV-2 full-length S protein (1-10 ng/mL) (supplied from GeneTex) for 24 h. Secretion of IL-1β (A) and CXCL8 (C) was determined by specific ELISAs. LPS (10 ng/mL) and NT (10 nM) were used as “positive” controls. All conditions were performed in triplicate for each dataset and repeated 3 times (n=3). Significance of comparisons is denoted by P < 0.05.(PNG 406 kb)

High Resolution (TIF 87 kb)

Supplementary Figure 2

SARS-CoV-2 S and RBD stimulate a differential secretion of pro-inflammatory mediators from human microglia. SV40 microglia (1.0 x 105 cells) were stimulated with recombinant SARS-CoV-2 full-length S protein (1-10 ng/mL) and RBD (1-10 ng/mL) (supplied from GeneTex) for 24 h. Secretion of IL-1β (A), CXCL8 (B), IL-6 (C), MMP9 (D), TNF-α (E), S100B (F) and IL-18 (G) was determined by specific ELISAs. LPS (10 ng/mL) and NT (10 nM) were used as “positive” controls. All conditions were performed in triplicate for each dataset and repeated 3 times (n=3). Significance of comparisons is denoted by P < 0.05. (PNG 423 kb)

High Resolution (TIF 87 kb)

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Tsilioni, I., Theoharides, T.C. Recombinant SARS-CoV-2 Spike Protein and Its Receptor Binding Domain Stimulate Release of Different Pro-Inflammatory Mediators via Activation of Distinct Receptors on Human Microglia Cells. Mol Neurobiol 60, 6704–6714 (2023). https://doi.org/10.1007/s12035-023-03493-7

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