Molecular Mechanisms of Proteins — Targets for SARS-CоV-2 (Review)

Abstract

The rapidly accumulating information about the new coronavirus infection and the ambiguous results obtained by various authors necessitate further research aiming at prevention and treatment of this disease. At the moment, there is convincing evidence that the pathogen affects not only the respiratory but also the central nervous system (CNS). The aim of the study is to provide an insight into the molecular mechanisms underlying the damage to the CNS caused by the new coronavirus SARS-CoV-2. Results. By analyzing the literature, we provide evidence that the brain is targeted by this virus. SARS-CoV-2 enters the body with the help of the target proteins: angiotensin-converting enzyme 2 (ACE2) and associated serine protease TMPRSS2 of the nasal epithelium. Brain damage develops before the onset of pulmonary symptoms. The virus spreads through the brain tissue into the piriform cortex, basal ganglia, midbrain, and hypothalamus. Later, the substantia nigra of the midbrain, amygdala, hippocampus, and cerebellum become affected. Massive death of neurons, astrogliosis and activation of microglia develop at the next stage of the disease. By day 4, an excessive production of proinflammatory cytokines in the brain, local neuroinflammation, breakdown of the blood-brain barrier, and impaired neuroplasticity are detected. These changes imply the involvement of a vascular component driven by excessive activity of matrix metalloproteinases, mediated by CD147. The main players in the pathogenesis of COVID-19 in the brain are products of angiotensin II (AT II) metabolism, largely angiotensin 1-7 (AT 1-7) and angiotensin IV (AT IV). There are conflicting data regarding their role in damage to the CNS in various diseases, including the coronavirus infection. The second participant in the pathogenesis of brain damage in COVID-19 is CD147 — the inducer of extracellular matrix metalloproteinases. This molecule is expressed on the endothelial cells of cerebral microvessels, as well as on leukocytes present in the brain during neuroinflammation. The CD147 molecule plays a significant role in maintaining the structural and functional integrity of the blood-brain barrier by controlling the basal membrane permeability and by mediating the astrocyte-endothelial interactions. Via the above mechanisms, an exposure to SARS-CoV-2 leads to direct damage to the neurovascular unit of the brain.

Development of a novel human CD147 knock-in NSG mouse model to test SARS-CoV-2 viral infection

“…However, CD147 is significantly upregulated in aggressive and chronic disease states, such as in cancers [ 67 , 68 ], atherosclerosis [ 69 ], diabetes [ 70 ], ischemic stroke [ 71 ], and chronic lung obstruction diseases [ 72 ]. Additionally, CD147 is strongly expressed on endothelial cells in the brain [ 73 ], gastrointestinal tract tissues [ 74 ], platelets [ 75 ], conjunctival tissues [ 76 ], kidney glomerular cells and podocytes [ 77 ], and cardiac pericytes [ 16 , 78 ], where it could serve a more dominant role in SARS-CoV-2 infection and mediate COVID-19-related neurological disturbance, digestive tract vascular damage, increased thrombosis, conjunctivitis, acute kidney injury, and cardiovascular disruption, respectively. Intriguingly, recent studies show that CD147 plays a functional role in facilitating SARS-CoV and SARS-CoV-2 entry [ 79 , 80 ], and antibodies against CD147 block the infection capabilities of SARS-CoV-2 [ 12 ].…”

Development of a Novel Human CD147 Knock-in NSG Mouse Model to Test SARS-CoV-2 Viral Infection

“…However, CD147 is signi cantly upregulated in aggressive and chronic disease states, such as in cancers [66, 67], atherosclerosis [68], diabetes [69], ischemic stroke [70], and chronic lung obstruction diseases [71]. Additionally, CD147 is strongly expressed on endothelial cells in the brain [72], gastrointestinal tract tissues [73], platelets [74], conjunctival tissues [75], kidney glomerular cells and podocytes [76], and cardiac pericytes [16,77], where it could serve a more dominant role in SARS-CoV-2 infection and mediate COVID-19-related neurological disturbance, digestive tract vascular damage, increased thrombosis, conjunctivitis, acute kidney injury, and cardiovascular disruption, respectively. Intriguingly, recent studies show that CD147 plays a functional role in facilitating SARS-CoV and SARS-CoV-2 entry [78, 79], and antibodies against CD147 block the infection capabilities of SARS-CoV-2 [12].…”

Is Autism a PIN1 Deficiency Syndrome? A Proposed Etiological Role for Glyphosate

“…A study on 28 cases of fatal myocarditis immediately following mRNA vaccination for SARS-CoV-2 established that all 28 deaths were most likely linked to the vaccine [261]. The spike protein is predicted to cause neuroinflammation and neurodegenerative disease, in part through its prion-like properties [262,263].…”