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SARS-CoV-2-associated lymphopenia: possible mechanisms and the role of CD147

Shouman et al., Cell Communication and Signaling, doi:10.1186/s12964-024-01718-3
Jul 2024  
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Ivermectin for COVID-19
4th treatment shown to reduce risk in August 2020
 
*, now with p < 0.00000000001 from 104 studies, recognized in 23 countries.
No treatment is 100% effective. Protocols combine treatments. * >10% efficacy, ≥3 studies.
4,400+ studies for 79 treatments. c19ivm.org
Review of possible mechanisms for lymphopenia in SARS-CoV-2 patients. Authors describe several indirect and direct mechanisms that may contribute to the T-cell depletion observed in COVID-19, including inflammatory cytokine storms, hyperlactic acidemia inhibiting lymphocyte proliferation, activation of apoptotic pathways, hematopoiesis and lymphoid organ dysfunction, lipid rafts facilitating viral entry, and direct viral infection of T-cells via cell surface receptors like CD147. The role of CD147 as a potential route for SARS-CoV-2 entry is explored in detail, including its expression on T-cells, function in modulating immune responses and inflammation, involvement in other viral infections, and interactions with the spike protein of new SARS-CoV-2 variants. Targeting the CD147 receptor is proposed as a potential therapeutic approach.
Potential treatments targeting CD147 include ivermectin, beta-blockers, statins, and humanized anti-CD147 antibodies.
Reviews covering ivermectin for COVID-19 include1-41.
Shouman et al., 4 Jul 2024, peer-reviewed, 10 authors. Contact: nelbadri@zewailcity.edu.eg.
This PaperIvermectinAll
SARS-CoV-2-associated lymphopenia: possible mechanisms and the role of CD147
Shaimaa Shouman, Nada El-Kholy, Alaa E Hussien, Azza M El-Derby, Shireen Magdy, Ahmed M Abou-Shanab, Ahmed O Elmehrath, Ahmad Abdelwaly, Mohamed Helal, Nagwa El-Badri
Cell Communication and Signaling, doi:10.1186/s12964-024-01718-3
T lymphocytes play a primary role in the adaptive antiviral immunity. Both lymphocytosis and lymphopenia were found to be associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). While lymphocytosis indicates an active anti-viral response, lymphopenia is a sign of poor prognosis. T-cells, in essence, rarely express ACE2 receptors, making the cause of cell depletion enigmatic. Moreover, emerging strains posed an immunological challenge, potentially alarming for the next pandemic. Herein, we review how possible indirect and direct key mechanisms could contribute to SARS-CoV-2-associated-lymphopenia. The fundamental mechanism is the inflammatory cytokine storm elicited by viral infection, which alters the host cell metabolism into a more acidic state. This "hyperlactic acidemia" together with the cytokine storm suppresses T-cell proliferation and triggers intrinsic/extrinsic apoptosis. SARS-CoV-2 infection also results in a shift from steady-state hematopoiesis to stress hematopoiesis. Even with low ACE2 expression, the presence of cholesterol-rich lipid rafts on activated T-cells may enhance viral entry and syncytia formation. Finally, direct viral infection of lymphocytes may indicate the participation of other receptors or auxiliary proteins on T-cells, that can work alone or in concert with other mechanisms. Therefore, we address the role of CD147-a novel route-for SARS-CoV-2 and its new variants. CD147 is not only expressed on T-cells, but it also interacts with other co-partners to orchestrate various biological processes. Given these features, CD147 is an appealing candidate for viral pathogenicity. Understanding the molecular and cellular mechanisms behind SARS-CoV-2-associated-lymphopenia will aid in the discovery of potential therapeutic targets to improve the resilience of our immune system against this rapidly evolving virus.
Declarations Ethical approval and consent to participants Not applicable Consent for publication Not applicable. Competing interests The authors declare no competing interests. Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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{ 'indexed': {'date-parts': [[2024, 7, 5]], 'date-time': '2024-07-05T00:14:54Z', 'timestamp': 1720138494277}, 'reference-count': 277, 'publisher': 'Springer Science and Business Media LLC', 'issue': '1', 'license': [ { 'start': { 'date-parts': [[2024, 7, 4]], 'date-time': '2024-07-04T00:00:00Z', 'timestamp': 1720051200000}, 'content-version': 'tdm', 'delay-in-days': 0, 'URL': 'https://creativecommons.org/licenses/by/4.0'}, { 'start': { 'date-parts': [[2024, 7, 4]], 'date-time': '2024-07-04T00:00:00Z', 'timestamp': 1720051200000}, 'content-version': 'vor', 'delay-in-days': 0, 'URL': 'https://creativecommons.org/licenses/by/4.0'}], 'funder': [ { 'DOI': '10.13039/501100003009', 'name': 'Science and Technology Development Fund', 'doi-asserted-by': 'publisher', 'award': [ '46721', '46721', '46721', '46721', '46721', '46721', '46721', '46721', '46721', '46721']}, { 'name': 'The Science, Technology & Innovation Funding Authority (STDF) in cooperation with ' 'The Egyptian Knowledge Bank (EKB).'}, {'name': 'Zewail City of Science & Technology'}], 'content-domain': {'domain': ['link.springer.com'], 'crossmark-restriction': False}, 'abstract': '<jats:title>Abstract</jats:title><jats:p>T lymphocytes play a primary role in the adaptive ' 'antiviral immunity. Both lymphocytosis and lymphopenia were found to be associated with ' 'severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). While lymphocytosis indicates ' 'an active anti-viral response, lymphopenia is a sign of poor prognosis. T-cells, in essence, ' 'rarely express ACE2 receptors, making the cause of cell depletion enigmatic. Moreover, ' 'emerging strains posed an immunological challenge, potentially alarming for the next ' 'pandemic. Herein, we review how possible indirect and direct key mechanisms could contribute ' 'to SARS-CoV-2-associated-lymphopenia. The fundamental mechanism is the inflammatory cytokine ' 'storm elicited by viral infection, which alters the host cell metabolism into a more acidic ' 'state. This “hyperlactic acidemia” together with the cytokine storm suppresses T-cell ' 'proliferation and triggers intrinsic/extrinsic apoptosis. SARS-CoV-2 infection also results ' 'in a shift from steady-state hematopoiesis to stress hematopoiesis. Even with low ACE2 ' 'expression, the presence of cholesterol-rich lipid rafts on activated T-cells may enhance ' 'viral entry and syncytia formation. Finally, direct viral infection of lymphocytes may ' 'indicate the participation of other receptors or auxiliary proteins on T-cells, that can work ' 'alone or in concert with other mechanisms. Therefore, we address the role of CD147―a novel ' 'route―for SARS-CoV-2 and its new variants. CD147 is not only expressed on T-cells, but it ' 'also interacts with other co-partners to orchestrate various biological processes. Given ' 'these features, CD147 is an appealing candidate for viral pathogenicity. Understanding the ' 'molecular and cellular mechanisms behind SARS-CoV-2-associated-lymphopenia will aid in the ' 'discovery of potential therapeutic targets to improve the resilience of our immune system ' 'against this rapidly evolving virus.</jats:p>\n' ' <jats:p><jats:bold>Graphical Abstract</jats:bold></jats:p>', 'DOI': '10.1186/s12964-024-01718-3', 'type': 'journal-article', 'created': {'date-parts': [[2024, 7, 4]], 'date-time': '2024-07-04T09:08:54Z', 'timestamp': 1720084134000}, 'update-policy': 'http://dx.doi.org/10.1007/springer_crossmark_policy', 'source': 'Crossref', 'is-referenced-by-count': 0, 'title': 'SARS-CoV-2-associated lymphopenia: possible mechanisms and the role of CD147', 'prefix': '10.1186', 'volume': '22', 'author': [ {'given': 'Shaimaa', 'family': 'Shouman', 'sequence': 'first', 'affiliation': []}, {'given': 'Nada', 'family': 'El-Kholy', 'sequence': 'additional', 'affiliation': []}, {'given': 'Alaa E.', 'family': 'Hussien', 'sequence': 'additional', 'affiliation': []}, {'given': 'Azza M.', 'family': 'El-Derby', 'sequence': 'additional', 'affiliation': []}, {'given': 'Shireen', 'family': 'Magdy', 'sequence': 'additional', 'affiliation': []}, {'given': 'Ahmed M.', 'family': 'Abou-Shanab', 'sequence': 'additional', 'affiliation': []}, {'given': 'Ahmed O.', 'family': 'Elmehrath', 'sequence': 'additional', 'affiliation': []}, {'given': 'Ahmad', 'family': 'Abdelwaly', 'sequence': 'additional', 'affiliation': []}, {'given': 'Mohamed', 'family': 'Helal', 'sequence': 'additional', 'affiliation': []}, {'given': 'Nagwa', 'family': 'El-Badri', 'sequence': 'additional', 'affiliation': []}], 'member': '297', 'published-online': {'date-parts': [[2024, 7, 4]]}, 'reference': [ { 'issue': '7', 'key': '1718_CR1', 'doi-asserted-by': 'publisher', 'first-page': '409', 'DOI': '10.1038/s41579-021-00573-0', 'volume': '19', 'author': 'WT Harvey', 'year': '2021', 'unstructured': 'Harvey WT, et al. 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' '2022;808:152072.', 'journal-title': 'Sci Total Environ'}, { 'issue': '11', 'key': '1718_CR274', 'doi-asserted-by': 'publisher', 'first-page': 'e2000094', 'DOI': '10.1002/bies.202000094', 'volume': '42', 'author': 'N Vasanthakumar', 'year': '2020', 'unstructured': 'Vasanthakumar N. Beta-adrenergic blockers as a potential treatment for ' 'COVID-19 patients. BioEssays. 2020;42(11):e2000094.', 'journal-title': 'BioEssays'}, { 'issue': '3', 'key': '1718_CR275', 'doi-asserted-by': 'publisher', 'first-page': '835', 'DOI': '10.3892/etm.2017.4062', 'volume': '13', 'author': 'X Liang', 'year': '2017', 'unstructured': 'Liang X, et al. Atorvastatin attenuates plaque vulnerability by ' 'downregulation of EMMPRIN expression via COX-2/PGE2 pathway. Exp Ther ' 'Med. 2017;13(3):835–44.', 'journal-title': 'Exp Ther Med'}, { 'issue': '7862', 'key': '1718_CR276', 'doi-asserted-by': 'publisher', 'first-page': '246', 'DOI': '10.1038/s41586-021-03493-4', 'volume': '594', 'author': 'A Stukalov', 'year': '2021', 'unstructured': 'Stukalov A, et al. Multilevel proteomics reveals host perturbations by ' 'SARS-CoV-2 and SARS-CoV. Nature. 2021;594(7862):246–52.', 'journal-title': 'Nature.'}, { 'issue': '12', 'key': '1718_CR277', 'doi-asserted-by': 'publisher', 'first-page': '1407', 'DOI': '10.1016/S2213-2600(21)00331-3', 'volume': '9', 'author': 'VC Marconi', 'year': '2021', 'unstructured': 'Marconi VC, et al. Efficacy and safety of baricitinib for the treatment ' 'of hospitalised adults with COVID-19 (COV-BARRIER): a randomised, ' 'double-blind, parallel-group, placebo-controlled phase 3 trial. 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Please send us corrections, updates, or comments. c19early involves the extraction of 100,000+ datapoints from thousands of papers. Community updates help ensure high accuracy. Treatments and other interventions are complementary. All practical, effective, and safe means should be used based on risk/benefit analysis. No treatment or intervention is 100% available and effective for all current and future variants. We do not provide medical advice. Before taking any medication, consult a qualified physician who can provide personalized advice and details of risks and benefits based on your medical history and situation. FLCCC and WCH provide treatment protocols.
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