heparitin-sulfate and Pneumonia--Viral

Pandemic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes coronavirus 19 disease (COVID-19) which presents a large spectrum of manifestations with fatal outcomes in vulnerable people over 70-years-old and with hypertension, diabetes, obesity, cardiovascular disease, COPD, and smoking status. Knowledge of the entry receptor is key to understand SARS-CoV-2 tropism, transmission and pathogenesis. Early evidence pointed to angiotensin-converting enzyme 2 (ACE2) as SARS-CoV-2 entry receptor. Here, we provide a critical summary of the current knowledge highlighting the limitations and remaining gaps that need to be addressed to fully characterize ACE2 function in SARS-CoV-2 infection and associated pathogenesis. We also discuss ACE2 expression and potential role in the context of comorbidities associated with poor COVID-19 outcomes. Finally, we discuss the potential co-receptors/attachment factors such as neuropilins, heparan sulfate and sialic acids and the putative alternative receptors, such as CD147 and GRP78.

Topics: Angiotensin-Converting Enzyme 2; Basigin; Betacoronavirus; Comorbidity; Coronavirus Infections; COVID-19; Endoplasmic Reticulum Chaperone BiP; Gene Expression Regulation, Enzymologic; Heparitin Sulfate; Humans; Hypertension; Neuropilin-1; Oligopeptides; Organ Specificity; Pandemics; Peptidyl-Dipeptidase A; Pneumonia, Viral; Protein Binding; Receptors, Virus; Renin-Angiotensin System; Respiratory System; RNA, Messenger; SARS-CoV-2; Sialic Acids; Spike Glycoprotein, Coronavirus; Virus Attachment; Virus Internalization

We show that SARS-CoV-2 spike protein interacts with both cellular heparan sulfate and angiotensin-converting enzyme 2 (ACE2) through its receptor-binding domain (RBD). Docking studies suggest a heparin/heparan sulfate-binding site adjacent to the ACE2-binding site. Both ACE2 and heparin can bind independently to spike protein in vitro, and a ternary complex can be generated using heparin as a scaffold. Electron micrographs of spike protein suggests that heparin enhances the open conformation of the RBD that binds ACE2. On cells, spike protein binding depends on both heparan sulfate and ACE2. Unfractionated heparin, non-anticoagulant heparin, heparin lyases, and lung heparan sulfate potently block spike protein binding and/or infection by pseudotyped virus and authentic SARS-CoV-2 virus. We suggest a model in which viral attachment and infection involves heparan sulfate-dependent enhancement of binding to ACE2. Manipulation of heparan sulfate or inhibition of viral adhesion by exogenous heparin presents new therapeutic opportunities.

Topics: Amino Acid Sequence; Angiotensin-Converting Enzyme 2; Betacoronavirus; Binding Sites; Cell Line; Coronavirus Infections; COVID-19; Heparin; Heparitin Sulfate; Humans; Kidney; Lung; Molecular Dynamics Simulation; Pandemics; Peptidyl-Dipeptidase A; Pneumonia, Viral; Protein Binding; Protein Domains; Recombinant Proteins; SARS-CoV-2; Spike Glycoprotein, Coronavirus; Virus Internalization

Reports suggest a role of endothelial dysfunction and loss of endothelial barrier function in COVID-19. It is well established that the endothelial glycocalyx-degrading enzyme heparanase contributes to vascular leakage and inflammation. Low molecular weight heparins (LMWH) serve as an inhibitor of heparanase. We hypothesize that heparanase contributes to the pathogenesis of COVID-19, and that heparanase may be inhibited by LMWH. To test this hypothesis, heparanase activity and heparan sulfate levels were measured in plasma of healthy controls (n = 10) and COVID-19 patients (n = 48). Plasma heparanase activity and heparan sulfate levels were significantly elevated in COVID-19 patients. Heparanase activity was associated with disease severity including the need for intensive care, lactate dehydrogenase levels, and creatinine levels. Use of prophylactic LMWH in non-ICU patients was associated with a reduced heparanase activity. Since there is no other clinically applied heparanase inhibitor currently available, therapeutic treatment of COVID-19 patients with low molecular weight heparins should be explored.

Topics: Aged; Betacoronavirus; Coronavirus Infections; COVID-19; Creatinine; Critical Care; Cross-Sectional Studies; Endothelium; Female; Glucuronidase; Heparin Antagonists; Heparin, Low-Molecular-Weight; Heparitin Sulfate; Humans; Interleukin-6; L-Lactate Dehydrogenase; Male; Middle Aged; Pandemics; Pneumonia, Viral; SARS-CoV-2; Tight Junctions