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Identification of a Novel Susceptibility Marker for SARS-CoV-2 Infection in Human Subjects and Risk Mitigation with a Clinically Approved JAK Inhibitor in Human/Mouse Cells
Coronavirus disease (COVID-19), caused by SARS-CoV-2, has affected over 65 million individuals and killed over 1.5 million persons (December 8, 2020; www.who.int)(1). While fatality rates are higher among the elderly and those with underlying comorbidities(2), host factors that promote susceptibilit...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Cold Spring Harbor Laboratory
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7743066/ https://www.ncbi.nlm.nih.gov/pubmed/33330862 http://dx.doi.org/10.1101/2020.12.09.416586 |
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author | Spalinger, Marianne R. Hai, Rong Li, Jiang Santos, Alina N. Nordgren, Tara M. Tremblay, Michel L. Eckmann, Lars Hanson, Elaine Scharl, Michael Wu, Xiwei Boland, Brigid S. McCole, Declan F. |
author_facet | Spalinger, Marianne R. Hai, Rong Li, Jiang Santos, Alina N. Nordgren, Tara M. Tremblay, Michel L. Eckmann, Lars Hanson, Elaine Scharl, Michael Wu, Xiwei Boland, Brigid S. McCole, Declan F. |
author_sort | Spalinger, Marianne R. |
collection | PubMed |
description | Coronavirus disease (COVID-19), caused by SARS-CoV-2, has affected over 65 million individuals and killed over 1.5 million persons (December 8, 2020; www.who.int)(1). While fatality rates are higher among the elderly and those with underlying comorbidities(2), host factors that promote susceptibility to SARS-CoV-2 infection and severe disease are poorly understood. Although individuals with certain autoimmune/inflammatory disorders show increased susceptibility to viral infections, there is incomplete knowledge of SARS-CoV-2 susceptibility in these diseases.(3–7) We report that the autoimmune PTPN2 risk variant rs1893217 promotes expression of the SARS-CoV-2 receptor, ACE2, and increases cellular entry mediated by SARS-CoV-2 spike protein. Elevated ACE2 expression and viral entry were mediated by increased JAK-STAT signalling, and were reversed by the JAK inhibitor, tofacitinib. Collectively, our findings uncover a novel risk biomarker for increased expression of the SARS-CoV-2 receptor and viral entry, and identify a clinically approved therapeutic agent to mitigate this risk. |
format | Online Article Text |
id | pubmed-7743066 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Cold Spring Harbor Laboratory |
record_format | MEDLINE/PubMed |
spelling | pubmed-77430662020-12-17 Identification of a Novel Susceptibility Marker for SARS-CoV-2 Infection in Human Subjects and Risk Mitigation with a Clinically Approved JAK Inhibitor in Human/Mouse Cells Spalinger, Marianne R. Hai, Rong Li, Jiang Santos, Alina N. Nordgren, Tara M. Tremblay, Michel L. Eckmann, Lars Hanson, Elaine Scharl, Michael Wu, Xiwei Boland, Brigid S. McCole, Declan F. bioRxiv Article Coronavirus disease (COVID-19), caused by SARS-CoV-2, has affected over 65 million individuals and killed over 1.5 million persons (December 8, 2020; www.who.int)(1). While fatality rates are higher among the elderly and those with underlying comorbidities(2), host factors that promote susceptibility to SARS-CoV-2 infection and severe disease are poorly understood. Although individuals with certain autoimmune/inflammatory disorders show increased susceptibility to viral infections, there is incomplete knowledge of SARS-CoV-2 susceptibility in these diseases.(3–7) We report that the autoimmune PTPN2 risk variant rs1893217 promotes expression of the SARS-CoV-2 receptor, ACE2, and increases cellular entry mediated by SARS-CoV-2 spike protein. Elevated ACE2 expression and viral entry were mediated by increased JAK-STAT signalling, and were reversed by the JAK inhibitor, tofacitinib. Collectively, our findings uncover a novel risk biomarker for increased expression of the SARS-CoV-2 receptor and viral entry, and identify a clinically approved therapeutic agent to mitigate this risk. Cold Spring Harbor Laboratory 2020-12-09 /pmc/articles/PMC7743066/ /pubmed/33330862 http://dx.doi.org/10.1101/2020.12.09.416586 Text en https://creativecommons.org/licenses/by-nd/4.0/This work is licensed under a Creative Commons Attribution-NoDerivatives 4.0 International License (https://creativecommons.org/licenses/by-nd/4.0/) , which allows reusers to copy and distribute the material in any medium or format in unadapted form only, and only so long as attribution is given to the creator. The license allows for commercial use. |
spellingShingle | Article Spalinger, Marianne R. Hai, Rong Li, Jiang Santos, Alina N. Nordgren, Tara M. Tremblay, Michel L. Eckmann, Lars Hanson, Elaine Scharl, Michael Wu, Xiwei Boland, Brigid S. McCole, Declan F. Identification of a Novel Susceptibility Marker for SARS-CoV-2 Infection in Human Subjects and Risk Mitigation with a Clinically Approved JAK Inhibitor in Human/Mouse Cells |
title | Identification of a Novel Susceptibility Marker for SARS-CoV-2 Infection in Human Subjects and Risk Mitigation with a Clinically Approved JAK Inhibitor in Human/Mouse Cells |
title_full | Identification of a Novel Susceptibility Marker for SARS-CoV-2 Infection in Human Subjects and Risk Mitigation with a Clinically Approved JAK Inhibitor in Human/Mouse Cells |
title_fullStr | Identification of a Novel Susceptibility Marker for SARS-CoV-2 Infection in Human Subjects and Risk Mitigation with a Clinically Approved JAK Inhibitor in Human/Mouse Cells |
title_full_unstemmed | Identification of a Novel Susceptibility Marker for SARS-CoV-2 Infection in Human Subjects and Risk Mitigation with a Clinically Approved JAK Inhibitor in Human/Mouse Cells |
title_short | Identification of a Novel Susceptibility Marker for SARS-CoV-2 Infection in Human Subjects and Risk Mitigation with a Clinically Approved JAK Inhibitor in Human/Mouse Cells |
title_sort | identification of a novel susceptibility marker for sars-cov-2 infection in human subjects and risk mitigation with a clinically approved jak inhibitor in human/mouse cells |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7743066/ https://www.ncbi.nlm.nih.gov/pubmed/33330862 http://dx.doi.org/10.1101/2020.12.09.416586 |
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