What role does endothelial infection play in SARS-CoV-2 infection?

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) can cause inflammatory lung diseases such as clot formation and hyperpermeability of pulmonary blood vessels, which can lead to edema and bleeding into the lungs. Inflammation also affects other organs, Cytokine storm..

This inflammation is characterized by dysfunction of endothelial cells in multiple organs. The cause of this endothelial damage is unknown. This may be due to a direct infection of endothelial cells or an indirect effect of cytokines.

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Integrin binding by SARS-CoV-2

Unlike early coronaviruses that are pathogenic to humans, SARS-CoV-2 Spike protein It is associated with host recognition and viral attachment via the angiotensin converting enzyme 2 (ACE2) receptor. A unique 3-residue RGD motif outside the ACE2 recognition site may allow the peplomer to bind to an endothelial protein called an integrin that binds to the RGD group.

In fact, a major integrin on endothelial cells called αVβ3 can bind to multiple RGD-binding ligands. It also binds to multiple extracellular matrix proteins such as fibrinogen, fibronectin, and vitronectin through binding pockets. These matrix proteins regulate cell adhesion, migration, proliferation, and angiogenesis.

Therefore, this mutation may enhance the binding of SARS-CoV-2 to host cells and may be involved in the higher infectivity of the virus compared to its predecessor. By two receptors.

Therefore, SARS-CoV-2 causes significant dysregulation of the endothelial barrier, losing its integrity and causing a hyperpermeability state. This leads to shock and the rapid spread of the virus to major organs.

Endothelial infection in COVID-19

Endothelial cells are key to several physiological processes, including immune cell activation, platelet aggregation and adhesion, white blood cell adhesion, and migration. They are also the target of many viruses and cause multiple organ failure.

Some studies have failed to show the growth of the virus in endothelial cells. This is due to the lack of expression of the angiotensin converting enzyme 2 (ACE2) receptor in these cells.

However, it may be argued that this is due to the essential difference between the in vitro grown endothelial monolayer and the inner endothelium of the blood vessels that process blood flowing under shear stress. Activation of endothelial cells by large amounts of cytokines; close contact with epithelial cells of lung capillaries.

Other researchers have reported that SARS-CoV-2 is associated with the endothelial cell marker CD31 in the lungs in infected mice and non-human primates (NHP). More importantly, this finding has been confirmed in the lung tissue of people who died of severe COVID-19.

Viral proteins were also found in endothelial cells. In addition, infected mice exhibited an upregulated KRAS signaling pathway in lung tissue known to mediate cell activation and dysfunction. Experimental evidence indicates that mouse endothelial cells are infected with SARS-CoV-2.

All endothelial cells express ACE2, but not all are viral targets. Instead, co-expression of other host proteases such as the transmembrane serine protease TMPRSS2 and cathepsin is required, cleaving the peplomer into its fusion conformation and allowing the virus to enter the host cell via endocytosis. To.

Endothelial cell injury

Following viral entry into endothelial cells, it begins translating the protein, replicates itself, and can directly induce cytotoxicity and apoptosis. In addition to this, endothelial cells activate T cells, but more than other antigen-presenting cells. In fact, endothelial cells activate only antigen-specific memory or effector T cells, not naive lymphocytes.

In doing so, endothelial cells may promote the destruction of infected cells by presenting viral proteins to CD8 T cells. In addition, endothelium cells of the microvascular system can cause memory or effector CD4T cells to migrate through the endothelium. Antiviral cytokines, including gamma interferon (IFN-γ), induce major histocompatibility complex (MHC) molecules of class I or II, co-stimulatory molecules normally required for T cell activation to occur. There is a possibility.

This means that endothelial dysfunction caused by COVID-19 blocks the activation of lymphocytes through endothelial cells, causing an imbalance in the adaptive immune response.

Cytokine storm

Cytokine storms cause a type of overshoot, leading to further endothelial dysfunction. These cytokines contain interleukin-6 (IL-6), which stimulates the pro-inflammatory mediator’s endothelial cell secretion and complement activation, further facilitating the disruption of the endothelial barrier.

The common lymphocyte depletion in COVID-19 may also be the result of excessive inflammation caused by damage to endothelial cells. A decrease in the number of CD4 lymphocytes can impair the response to infection and at the same time stimulate further inflammation. Therefore, a severe and severe COVID-19 hyperinflammatory response may be due to endothelial cell infection and dysfunction.

Loss of endothelial barrier integrity

SARS-CoV-2 infection causes coagulopathy and systemic microangiopathy, as well as immune dysfunction and extensive endothelial damage. Poor disease outcomes are mediated primarily by increased vascular permeability secondary to infection-related inflammation.

This high permeability is associated with the leakage of both cellular and non-cellular components of blood within the small blood vessels of the lungs, causing the alveoli to become congested with fluid. Patients can drown in fluid from leaked blood vessels, causing choking and endangering their lives.

Hypercoagulation

At the same time, the coagulation cascade becomes dysregulated, causing leukocyte infiltration and the formation of microthrombus throughout the circulation. Endothelial cell dysfunction can cause further inflammation and leukocyte recruitment and adhesion.

Endothelial cells express glycosaminoglycans and thrombomodulin on the cell surface, thus inhibiting thrombin, a coagulation cascade component, and tissue factor protein inhibitors. Many relaxing factors such as nitric oxide (NO) and prostacyclin (PGI2) are also produced by these cells, blocking the adhesion and migration of white blood cells and platelets, the growth of smooth muscle, and anti-inflammatory and anti-apoptotic effects. Demonstrate.

When endothelial cells are damaged by the invasion of the virus, they cease to exert anticoagulant effects and are prone to widespread microthrombus, vitreous formation in the small arterioles of the lungs, and thrombosis manifested as diffuse alveolar damage. be connected.

This hypercoagulable state causes elevated D-dimer levels, and COVID-19 causes poor outcome and increased mortality. Multiples, from exposure of tissue factor to coagulation factors in the blood to loss of endothelial integrity, and thus activation of the endogenous coagulation pathway by the exposed matrix beneath the endothelial cell layer, to the release of destructive vans. Willebrand factor (vWF) due to endothelial dysfunction in which the coagulation promoting mechanism works. This molecule acts to bridge platelets for aggregation and clot formation.

Infection of endothelial cells may be associated with viral invasion of adjacent tissues, namely smooth muscle cells and cardiomyocytes of arteries.

Therapeutic implications

Therefore, SARS-CoV-2 infection of endothelial cells may be the root cause of cardiovascular complications of COVID-19, including end-stage multiple organ failure. Endothelial apoptosis was seen in patients who died of COVID-19, and it is plausible that microthrombus scattered throughout the pulmonary vascular bed, along with dysfunction of the right ventricle, is associated with direct infection of the endothelial cells.

Peplomer binding to αVβ3 can be inhibited by Cylengitide, an RGD tripeptide, a specific αVβ3 antagonist that has a high affinity for this integrin and suppresses virus-endothelial binding at very low doses. I can do it.

Other treatment strategies include serine protease inhibitors. Renin-angiotensin-aldosteron system Inhibitors, statins, heparin, corticosteroids, and IL-6 inhibitors. All of these act at least partially through the stabilization and protection of endothelial integrity.

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