The spike protein of SARS-CoV-2 induces endothelial inflammation through integrin α5β1 and NF-κB signaling

Robles, Juan Pablo; Zamora, Magdalena; Adán‐Castro, Elva; Siqueiros‐Márquez, Lourdes; Escalera, Gonzálo Martínez de la; Clapp, Carmen

doi:10.1016/j.jbc.2022.101695

Cited by 91 publications

(93 citation statements)

References 59 publications

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“…Subsequently, inter-endothelial junction weakening and hyperpermeability has been observed, which likely elucidates the pulmonary and cardiovascular complications in COVID-19 1,2,7 . Inhibiting spike protein attachment hinders this response 1,7 . Therefore we sought to describe the pathway correlating integrins to COVID-19 vascular dysregulation via VE-Cadherin.…”

Section: Discussionmentioning

confidence: 95%

“…In particular, integrins αVβ3 and α5β1 recognize the RGD motif uniquely expressed by SARS-CoV-2, which mediates infection of epithelial and endothelial cells in vitro and in vivo 1,[5][6][7][8] . Subsequently, inter-endothelial junction weakening and hyperpermeability has been observed, which likely elucidates the pulmonary and cardiovascular complications in COVID-19 1,2,7 . Inhibiting spike protein attachment hinders this response 1,7 .…”

Section: Discussionmentioning

confidence: 99%

“…The relationship between SARS-CoV-2 spike protein and its host receptor ACE2 has been well defined, and a dual-receptor mechanism has been proposed with another cell surface receptor, integrins. In particular, integrins αVβ3 and α5β1 recognize the RGD motif uniquely expressed by SARS-CoV-2, which mediates infection of epithelial and endothelial cells in vitro and in vivo 1,[5][6][7][8] . Subsequently, inter-endothelial junction weakening and hyperpermeability has been observed, which likely elucidates the pulmonary and cardiovascular complications in COVID-19 1,2,7 .…”

Section: Discussionmentioning

confidence: 99%

“…However, infection dramatically altered VE-Cadherin organization by triggering its internalisation, which led to the dysfunctional barrier phenotype. Furthermore, the spike protein of SARS-CoV-2 has been demonstrated to signal the upregulation of RhoA in infected venous endothelial cells by downregulating Rac1, which promoted permeability and leakage 7 . Following integrin ligation, VE-Cadherin is known to coordinate with Rac1 to inhibit RhoA to regulate cell spreading 16 (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…Activated through binding an RGD-containing ligand, integrins can control downstream signalling transduction cascades that tether VE-Cadherin at the cell junctions through RhoGTPase cycling 3,4 . The spike protein contains an integrinbinding RGD motif that adheres to integrins αVβ3 and α5β1 on pulmonary epithelial cells and endothelial cells, where integrin antagonists Cilengitide and ATN-161 have demonstrated success in inhibiting this interaction in vitro and in vivo, thereby suggesting integrin-targeted therapeutics in COVID-19 1,[5][6][7][8] . We aimed to identify the direct pathway that associates integrins with vascular dysregulation during SARS-CoV-2 infection, and whether targeting the spike protein RGD motif is sufficient to reduce this disease phenotype.…”

Section: Introductionmentioning

confidence: 99%

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Vascular dysregulation following SARS-CoV-2 infection involves integrin signalling through a VE-Cadherin mediated pathway

Nader

Kerrigan

2022

Preprint

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The vascular barrier is heavily injured following SARS-CoV-2 infection and contributes enormously to life-threatening complications in COVID-19. This endothelial dysfunction is associated with the phlogistic phenomenon of cytokine storms, thrombotic complications, abnormal coagulation, hypoxemia, and multiple organ failure. The mechanisms surrounding COVID-19 associated endotheliitis have been widely attributed to ACE2-mediated pathways. However, integrins have emerged as possible receptor candidates for SARS-CoV-2, and their complex intracellular signaling events are essential for maintaining endothelial homeostasis. Here, we showed that the spike protein of SARS-CoV-2 depends on its RGD motif to drive barrier dysregulation through hijacking integrin αVβ3. This triggers the redistribution and internalization of major junction protein VE-Cadherin which leads to the barrier disruption phenotype. Both extracellular and intracellular inhibitors of integrin αVβ3 prevented these effects, similarly to the RGD-cyclic peptide compound Cilengitide, which suggests that the spike protein – through its RGD motif – binds to αVβ3 and elicits vascular leakage events. These findings support integrins as an additional receptor for SARS-CoV-2, particularly as integrin engagement can elucidate many of the adverse endothelial dysfunction events that stem from COVID-19.

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Section: Discussionmentioning

confidence: 95%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Vascular dysregulation following SARS-CoV-2 infection involves integrin signalling through a VE-Cadherin mediated pathway

Nader

Kerrigan

2022

Preprint

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Extracellular Vesicles: The Invisible Heroes and Villains of COVID‐19 Central Neuropathology

Chang,

Chen,

et al. 2023

Advanced Science

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Acknowledging the neurological symptoms of COVID‐19 and the long‐lasting neurological damage even after the epidemic ends are common, necessitating ongoing vigilance. Initial investigations suggest that extracellular vesicles (EVs), which assist in the evasion of the host's immune response and achieve immune evasion in SARS‐CoV‐2 systemic spreading, contribute to the virus's attack on the central nervous system (CNS). The pro‐inflammatory, pro‐coagulant, and immunomodulatory properties of EVs contents may directly drive neuroinflammation and cerebral thrombosis in COVID‐19. Additionally, EVs have attracted attention as potential candidates for targeted therapy in COVID‐19 due to their innate homing properties, low immunogenicity, and ability to cross the blood‐brain barrier (BBB) freely. Mesenchymal stromal/stem cell (MSCs) secreted EVs are widely applied and evaluated in patients with COVID‐19 for their therapeutic effect, considering the limited antiviral treatment. This review summarizes the involvement of EVs in COVID‐19 neuropathology as carriers of SARS‐CoV‐2 or other pathogenic contents, as predictors of COVID‐19 neuropathology by transporting brain‐derived substances, and as therapeutic agents by delivering biotherapeutic substances or drugs. Understanding the diverse roles of EVs in the neuropathological aspects of COVID‐19 provides a comprehensive framework for developing, treating, and preventing central neuropathology and the severe consequences associated with the disease.

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Extracellular vesicles and endothelial dysfunction in infectious diseases

Zhang,

Chi,

et al. 2024

J of Extracellular Bio

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Cardiovascular diseases (CVDs) remain the leading cause of mortality and morbidity globally. Studies have shown that infections especially bacteraemia and sepsis are associated with increased risks for endothelial dysfunction and related CVDs including atherosclerosis. Extracellular vesicles (EVs) are small, sealed membrane‐derived structures that are released into body fluids and blood from cells and/or microbes and are critically involved in a variety of important cell functions and disease development, including intercellular communications, immune responses and inflammation. It is known that EVs‐mediated mechanism(s) is important in the development of endothelial dysfunction in infections with a diverse spectrum of microorganisms including Escherichia coli, Candida albicans, SARS‐CoV‐2 (the virus for COVID‐19) and Helicobacter pylori. H. pylori infection is one of the most common infections globally. During H. pylori infection, EVs can carry H. pylori components, such as lipopolysaccharide, cytotoxin‐associated gene A, or vacuolating cytotoxin A, and transfer these substances into endothelial cells, triggering inflammatory responses and endothelial dysfunction. This review is to illustrate the important role of EVs in the pathogenesis of infectious diseases, and the development of endothelial dysfunction in infectious diseases especially H. pylori infection, and to discuss the potential mechanisms and clinical implications.

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The spike protein of SARS-CoV-2 induces endothelial inflammation through integrin α5β1 and NF-κB signaling

Cited by 91 publications

References 59 publications

Vascular dysregulation following SARS-CoV-2 infection involves integrin signalling through a VE-Cadherin mediated pathway

Vascular dysregulation following SARS-CoV-2 infection involves integrin signalling through a VE-Cadherin mediated pathway

Extracellular Vesicles: The Invisible Heroes and Villains of COVID‐19 Central Neuropathology

Extracellular vesicles and endothelial dysfunction in infectious diseases

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