Back to the Basics of SARS-CoV-2 Biochemistry: Microvascular Occlusive Glycan Bindings Govern Its Morbidities and Inform Therapeutic Responses

{ 'DOI': '10.3390/v16040647', 'ISSN': ['1999-4915'], 'URL': 'http://dx.doi.org/10.3390/v16040647', 'abstract': '<jats:p>Consistent with the biochemistry of coronaviruses as well established over decades, ' 'SARS-CoV-2 makes its initial attachment to host cells through the binding of its spike ' 'protein (SP) to sialylated glycans (containing the monosaccharide sialic acid) on the cell ' 'surface. The virus can then slide over and enter via ACE2. SARS-CoV-2 SP attaches ' 'particularly tightly to the trillions of red blood cells (RBCs), platelets and endothelial ' 'cells in the human body, each cell very densely coated with sialic acid surface molecules but ' 'having no ACE2 or minimal ACE2. These interlaced attachments trigger the blood cell ' 'aggregation, microvascular occlusion and vascular damage that underlie the hypoxia, blood ' 'clotting and related morbidities of severe COVID-19. Notably, the two human betacoronaviruses ' 'that express a sialic acid-cleaving enzyme are benign, while the other three—SARS, SARS-CoV-2 ' 'and MERS—are virulent. RBC aggregation experimentally induced in several animal species using ' 'an injected polysaccharide caused most of the same morbidities of severe COVID-19. This ' 'glycan biochemistry is key to disentangling controversies that have arisen over the efficacy ' 'of certain generic COVID-19 treatment agents and the safety of SP-based COVID-19 vaccines. ' 'More broadly, disregard for the active physiological role of RBCs yields unreliable or ' 'erroneous reporting of pharmacokinetic parameters as routinely obtained for most drugs and ' 'other bioactive agents using detection in plasma, with whole-blood levels being up to 30-fold ' 'higher. Appreciation of the active role of RBCs can elucidate the microvascular underpinnings ' 'of other health conditions, including cardiovascular disease, and therapeutic opportunities ' 'to address them.</jats:p>', 'alternative-id': ['v16040647'], 'author': [ { 'ORCID': 'http://orcid.org/0000-0001-6841-7054', 'affiliation': [ { 'name': 'US Public Health Service, Commissioned Corps, Inactive Reserve, ' 'Blacksburg, VA 24060, USA'}], 'authenticated-orcid': False, 'family': 'Scheim', 'given': 'David E.', 'sequence': 'first'}, { 'ORCID': 'http://orcid.org/0000-0003-1086-0138', 'affiliation': [ { 'name': 'Children’s Health Research Clinical Unit, Faculty of Medicine, ' 'The University of Queensland, South Brisbane, QLD 4101, ' 'Australia'}, { 'name': 'Department of Psychiatry, Flinders University, Bedford Park, SA ' '5042, Australia'}], 'authenticated-orcid': False, 'family': 'Parry', 'given': 'Peter I.', 'sequence': 'additional'}, { 'affiliation': [ { 'name': 'Kolling Institute, Faculty of Medicine and Health, The ' 'University of Sydney, St Leonards, NSW 2064, Australia'}], 'family': 'Rabbolini', 'given': 'David J.', 'sequence': 'additional'}, { 'affiliation': [ { 'name': 'College of Health Sciences, University of KwaZulu-Natal, Durban ' '4041, South Africa'}], 'family': 'Aldous', 'given': 'Colleen', 'sequence': 'additional'}, { 'ORCID': 'http://orcid.org/0009-0009-9427-1947', 'affiliation': [ { 'name': 'Satoshi Omura Memorial Research Institute, Kitasato University, ' 'Tokyo 108-8641, Japan'}, { 'name': 'Louis Pasteur Center for Medical Research, Kyoto 606-8225, ' 'Japan'}], 'authenticated-orcid': False, 'family': 'Yagisawa', 'given': 'Morimasa', 'sequence': 'additional'}, { 'affiliation': [ { 'name': 'Emeritus Professor, School of Medicine and Public Health, ' 'University of Newcastle, Newcastle, NE1 7RU, Australia'}], 'family': 'Clancy', 'given': 'Robert', 'sequence': 'additional'}, { 'ORCID': 'http://orcid.org/0000-0002-0519-4698', 'affiliation': [{'name': 'Centre for Digestive Diseases, Five Dock, NSW 2046, Australia'}], 'authenticated-orcid': False, 'family': 'Borody', 'given': 'Thomas J.', 'sequence': 'additional'}, { 'affiliation': [ { 'name': 'Emeritus Professor of Medicine, University of Queensland, ' 'Herston, QLD 4029, Australia'}], 'family': 'Hoy', 'given': 'Wendy E.', 'sequence': 'additional'}], 'container-title': 'Viruses', 'container-title-short': 'Viruses', 'content-domain': {'crossmark-restriction': False, 'domain': []}, 'created': {'date-parts': [[2024, 4, 22]], 'date-time': '2024-04-22T13:53:52Z', 'timestamp': 1713794032000}, 'deposited': { 'date-parts': [[2024, 4, 22]], 'date-time': '2024-04-22T14:05:13Z', 'timestamp': 1713794713000}, 'indexed': {'date-parts': [[2024, 4, 23]], 'date-time': '2024-04-23T00:37:09Z', 'timestamp': 1713832629606}, 'is-referenced-by-count': 0, 'issue': '4', 'issued': {'date-parts': [[2024, 4, 22]]}, 'journal-issue': {'issue': '4', 'published-online': {'date-parts': [[2024, 4]]}}, 'language': 'en', 'license': [ { 'URL': 'https://creativecommons.org/licenses/by/4.0/', 'content-version': 'vor', 'delay-in-days': 0, 'start': { 'date-parts': [[2024, 4, 22]], 'date-time': '2024-04-22T00:00:00Z', 'timestamp': 1713744000000}}], 'link': [ { 'URL': 'https://www.mdpi.com/1999-4915/16/4/647/pdf', 'content-type': 'unspecified', 'content-version': 'vor', 'intended-application': 'similarity-checking'}], 'member': '1968', 'original-title': [], 'page': '647', 'prefix': '10.3390', 'published': {'date-parts': [[2024, 4, 22]]}, 'published-online': {'date-parts': [[2024, 4, 22]]}, 'publisher': 'MDPI AG', 'reference': [ { 'DOI': '10.3390/ijms242317039', 'doi-asserted-by': 'crossref', 'key': 'ref_1', 'unstructured': 'Scheim, D.E., Vottero, P., Santin, A.D., and Hirsh, A.G. 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