Nucleocapsid and Spike Proteins of the Coronavirus SARS-CoV-2 Induce IL6 in Monocytes and Macrophages—Potential Implications for Cytokine Storm Syndrome

Karwaciak, Iwona; Sałkowska, Anna; Karaś, Kaja; Dastych, Jarosław; Ratajewski, Marcin

doi:10.3390/vaccines9010054

Cited by 52 publications

(45 citation statements)

References 53 publications

(54 reference statements)

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“…In our study, the incubation of MDM with the S1 protein produced a massive release of cytokines and chemokines, namely IL-1β, IL-6, TNFα, IL-8, and IL-10. Similar results were described by Karwaciak et al in GM-CSF differentiated human macrophages [ 42 ] and bone marrow-derived mice macrophages [ 43 ]. Collectively, these findings are consistent with the elevated plasma levels of inflammatory markers observed in COVID-19 patients [ 44 , 45 ], where the profile of IL-6, CCL2/MCP-1, and CXCL10/IP-10 are associated with the severity of the disease [ 46 ].…”

Section: Discussionsupporting

confidence: 90%

Endothelial Cell Activation by SARS-CoV-2 Spike S1 Protein: A Crosstalk between Endothelium and Innate Immune Cells

et al. 2021

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Background. Emerging evidences suggest that in severe COVID-19, multi-organ failure is associated with a hyperinflammatory state (the so-called “cytokine storm”) in combination with the development of a prothrombotic state. The central role of endothelial dysfunction in the pathogenesis of the disease is to date accepted, but the precise mechanisms underlying the associated coagulopathy remain unclear. Whether the alterations in vascular homeostasis directly depend upon the SARS-CoV-2 infection of endothelial cells or, rather, occur secondarily to the activation of the inflammatory response is still a matter of debate. Here, we address the effect of the SARS-CoV-2 spike S1 protein on the activation of human lung microvascular endothelial cells (HLMVEC). In particular, the existence of an endothelium-macrophage crosstalk in the response to the spike protein has been explored. Methods and Results. The effect of the spike protein is addressed in human lung microvascular endothelial cells (HLMVEC), either directly or after incubation with a conditioned medium (CM) of human monocyte-derived macrophages (MDM) previously activated by the spike S1 protein (CM-MDM). Both MDM and HLMVEC are activated in response to the S1 protein, with an increased expression of pro-inflammatory mediators. However, when HLMVEC are exposed to CM-MDM, an enhanced cell activation occurs in terms of the expression of adhesion molecules, pro-coagulant markers, and chemokines. Under this experimental condition, ICAM-1 and VCAM-1, the chemokines CXCL8/IL-8, CCL2/MCP1, and CXCL10/IP-10 as well as the protein tissue factor (TF) are markedly induced. Instead, a decrease of thrombomodulin (THBD) is observed. Conclusion. Our data suggest that pro-inflammatory mediators released by spike-activated macrophages amplify the activation of endothelial cells, likely contributing to the impairment of vascular integrity and to the development of a pro-coagulative endothelium.

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Section: Discussionsupporting

confidence: 90%

Endothelial Cell Activation by SARS-CoV-2 Spike S1 Protein: A Crosstalk between Endothelium and Innate Immune Cells

et al. 2021

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“…PTX3 was expressed at high levels by myeloid cells in blood and lungs and its plasma levels have strong and independent prognostic significance for death in COVID-19 patients (Brunetta et al, 2021; Schirinzi et al, 2021). It remains to be elucidated whether PTX3 plays a role in Nucleocapsid-mediated complement activation and cytokine production (Gao et al, 2020; Karwaciak et al, 2021; McBride et al, 2014).…”

Section: Discussionmentioning

confidence: 99%

Recognition and inhibition of SARS-CoV-2 by humoral innate immunity pattern recognition molecules

Stravalaci

Pagani

Paraboschi

et al. 2021

Preprint

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The humoral arm of innate immunity includes diverse molecules with antibody-like functions, some of which serve as disease severity biomarkers in COVID-19. The present study was designed to conduct a systematic investigation of the interaction of humoral fluid phase pattern recognition molecules (PRM) with SARS-CoV-2. Out of 10 PRM tested, the long pentraxin PTX3 and Mannose Binding Lectin (MBL) bound the viral Nucleoprotein and Spike, respectively. MBL bound trimeric Spike, including that of variants of concern, in a glycan-dependent way and inhibited SARS-CoV-2 in three in vitro models. Moreover, upon binding to Spike, MBL activated the lectin pathway of complement activation. Genetic polymorphisms at the MBL locus were associated with disease severity. These results suggest that selected humoral fluid phase PRM can play an important role in resistance to, and pathogenesis of, COVID-19, a finding with translational implications.

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“…Notably, an in vitro study conducted on SARS-CoV-1 reported that the SARS-CoV-1 nucleocapsid (N) protein can directly interact with NF-kB and facilitates nuclear translocation, eventually manipulating cytokine release [ 23 ]. Similarly, human monocytes and macrophages cultured in the presence of SARS-CoV-2 N protein and S protein expressed high levels of cytokines such as IL-6, IL1B, IL-10 and TNF [ 24 ]. Supportively, SARS-CoV-2 N protein promotes NF-kB signaling by targeting IKK complex eventually initiating cytokine release in vitro [ 25 ].…”

Section: Innate Immune Responsementioning

confidence: 99%

Interferon β, an enhancer of the innate immune response against SARS-CoV-2 infection

Kali

Dröge

Murugan

2021

Microbial Pathogenesis

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COVID-19 exhibits a global health threat among the elderly and the population with underlying health conditions. During infection, the host's innate immune response acts as a frontline of defense by releasing cytokines such as type I interferon (IFN α and β) thereby initiating antiviral activity. However, this particular interferon response is interrupted by factors such as SARS-CoV-2 non-structural proteins, aging, diabetes, and germ-line errors eventually making the host more susceptible to illness. Therefore, enhancing the host's innate immune response by administering type I IFN could be an effective treatment against COVID-19. Here, we highlight the importance of innate immune response and the role of IFN β monotherapy against COVID-19.

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Nucleocapsid and Spike Proteins of the Coronavirus SARS-CoV-2 Induce IL6 in Monocytes and Macrophages—Potential Implications for Cytokine Storm Syndrome

Cited by 52 publications

References 53 publications

Endothelial Cell Activation by SARS-CoV-2 Spike S1 Protein: A Crosstalk between Endothelium and Innate Immune Cells

Endothelial Cell Activation by SARS-CoV-2 Spike S1 Protein: A Crosstalk between Endothelium and Innate Immune Cells

Recognition and inhibition of SARS-CoV-2 by humoral innate immunity pattern recognition molecules

Interferon β, an enhancer of the innate immune response against SARS-CoV-2 infection

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