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SARS-CoV-2 drives JAK1/2-dependent local complement hyperactivation
Patients with coronavirus disease 2019 (COVID-19) present a wide range of acute clinical manifestations affecting the lungs, liver, kidneys and gut. Angiotensin converting enzyme (ACE) 2, the best-characterized entry receptor for the disease-causing virus SARS-CoV-2, is highly expressed in the afore...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Association for the Advancement of Science
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8139422/ https://www.ncbi.nlm.nih.gov/pubmed/33827897 http://dx.doi.org/10.1126/sciimmunol.abg0833 |
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author | Yan, Bingyu Freiwald, Tilo Chauss, Daniel Wang, Luopin West, Erin Mirabelli, Carmen Zhang, Charles J Nichols, Eva-Maria Malik, Nazish Gregory, Richard Bantscheff, Marcus Ghidelli-Disse, Sonja Kolev, Martin Frum, Tristan Spence, Jason R Sexton, Jonathan Z. Alysandratos, Konstantinos D. Kotton, Darrell N. Pittaluga, Stefania Bibby, Jack Niyonzima, Nathalie Olson, Matthew R Kordasti, Shahram Portilla, Didier Wobus, Christiane E Laurence, Arian Lionakis, Michail S Kemper, Claudia Afzali, Behdad Kazemian, Majid |
author_facet | Yan, Bingyu Freiwald, Tilo Chauss, Daniel Wang, Luopin West, Erin Mirabelli, Carmen Zhang, Charles J Nichols, Eva-Maria Malik, Nazish Gregory, Richard Bantscheff, Marcus Ghidelli-Disse, Sonja Kolev, Martin Frum, Tristan Spence, Jason R Sexton, Jonathan Z. Alysandratos, Konstantinos D. Kotton, Darrell N. Pittaluga, Stefania Bibby, Jack Niyonzima, Nathalie Olson, Matthew R Kordasti, Shahram Portilla, Didier Wobus, Christiane E Laurence, Arian Lionakis, Michail S Kemper, Claudia Afzali, Behdad Kazemian, Majid |
author_sort | Yan, Bingyu |
collection | PubMed |
description | Patients with coronavirus disease 2019 (COVID-19) present a wide range of acute clinical manifestations affecting the lungs, liver, kidneys and gut. Angiotensin converting enzyme (ACE) 2, the best-characterized entry receptor for the disease-causing virus SARS-CoV-2, is highly expressed in the aforementioned tissues. However, the pathways that underlie the disease are still poorly understood. Here, we unexpectedly found that the complement system was one of the intracellular pathways most highly induced by SARS-CoV-2 infection in lung epithelial cells. Infection of respiratory epithelial cells with SARS-CoV-2 generated activated complement component C3a and could be blocked by a cell-permeable inhibitor of complement factor B (CFBi), indicating the presence of an inducible cell-intrinsic C3 convertase in respiratory epithelial cells. Within cells of the bronchoalveolar lavage of patients, distinct signatures of complement activation in myeloid, lymphoid and epithelial cells tracked with disease severity. Genes induced by SARS-CoV-2 and the drugs that could normalize these genes both implicated the interferon-JAK1/2-STAT1 signaling system and NF-B as the main drivers of their expression. Ruxolitinib, a JAK1/2 inhibitor, normalized interferon signature genes and all complement gene transcripts induced by SARS-CoV-2 in lung epithelial cell lines, but did not affect NF-B-regulated genes. Ruxolitinib, alone or in combination with the antiviral remdesivir, inhibited C3a protein produced by infected cells. Together, we postulate that combination therapy with JAK inhibitors and drugs that normalize NF-B-signaling could potentially have clinical application for severe COVID-19. |
format | Online Article Text |
id | pubmed-8139422 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | American Association for the Advancement of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-81394222021-05-25 SARS-CoV-2 drives JAK1/2-dependent local complement hyperactivation Yan, Bingyu Freiwald, Tilo Chauss, Daniel Wang, Luopin West, Erin Mirabelli, Carmen Zhang, Charles J Nichols, Eva-Maria Malik, Nazish Gregory, Richard Bantscheff, Marcus Ghidelli-Disse, Sonja Kolev, Martin Frum, Tristan Spence, Jason R Sexton, Jonathan Z. Alysandratos, Konstantinos D. Kotton, Darrell N. Pittaluga, Stefania Bibby, Jack Niyonzima, Nathalie Olson, Matthew R Kordasti, Shahram Portilla, Didier Wobus, Christiane E Laurence, Arian Lionakis, Michail S Kemper, Claudia Afzali, Behdad Kazemian, Majid Sci Immunol Research Articles Patients with coronavirus disease 2019 (COVID-19) present a wide range of acute clinical manifestations affecting the lungs, liver, kidneys and gut. Angiotensin converting enzyme (ACE) 2, the best-characterized entry receptor for the disease-causing virus SARS-CoV-2, is highly expressed in the aforementioned tissues. However, the pathways that underlie the disease are still poorly understood. Here, we unexpectedly found that the complement system was one of the intracellular pathways most highly induced by SARS-CoV-2 infection in lung epithelial cells. Infection of respiratory epithelial cells with SARS-CoV-2 generated activated complement component C3a and could be blocked by a cell-permeable inhibitor of complement factor B (CFBi), indicating the presence of an inducible cell-intrinsic C3 convertase in respiratory epithelial cells. Within cells of the bronchoalveolar lavage of patients, distinct signatures of complement activation in myeloid, lymphoid and epithelial cells tracked with disease severity. Genes induced by SARS-CoV-2 and the drugs that could normalize these genes both implicated the interferon-JAK1/2-STAT1 signaling system and NF-B as the main drivers of their expression. Ruxolitinib, a JAK1/2 inhibitor, normalized interferon signature genes and all complement gene transcripts induced by SARS-CoV-2 in lung epithelial cell lines, but did not affect NF-B-regulated genes. Ruxolitinib, alone or in combination with the antiviral remdesivir, inhibited C3a protein produced by infected cells. Together, we postulate that combination therapy with JAK inhibitors and drugs that normalize NF-B-signaling could potentially have clinical application for severe COVID-19. American Association for the Advancement of Science 2021-04-07 2021-04-07 /pmc/articles/PMC8139422/ /pubmed/33827897 http://dx.doi.org/10.1126/sciimmunol.abg0833 Text en Copyright 2021, American Association for the Advancement of Science https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution license (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Research Articles Yan, Bingyu Freiwald, Tilo Chauss, Daniel Wang, Luopin West, Erin Mirabelli, Carmen Zhang, Charles J Nichols, Eva-Maria Malik, Nazish Gregory, Richard Bantscheff, Marcus Ghidelli-Disse, Sonja Kolev, Martin Frum, Tristan Spence, Jason R Sexton, Jonathan Z. Alysandratos, Konstantinos D. Kotton, Darrell N. Pittaluga, Stefania Bibby, Jack Niyonzima, Nathalie Olson, Matthew R Kordasti, Shahram Portilla, Didier Wobus, Christiane E Laurence, Arian Lionakis, Michail S Kemper, Claudia Afzali, Behdad Kazemian, Majid SARS-CoV-2 drives JAK1/2-dependent local complement hyperactivation |
title | SARS-CoV-2 drives JAK1/2-dependent local complement hyperactivation |
title_full | SARS-CoV-2 drives JAK1/2-dependent local complement hyperactivation |
title_fullStr | SARS-CoV-2 drives JAK1/2-dependent local complement hyperactivation |
title_full_unstemmed | SARS-CoV-2 drives JAK1/2-dependent local complement hyperactivation |
title_short | SARS-CoV-2 drives JAK1/2-dependent local complement hyperactivation |
title_sort | sars-cov-2 drives jak1/2-dependent local complement hyperactivation |
topic | Research Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8139422/ https://www.ncbi.nlm.nih.gov/pubmed/33827897 http://dx.doi.org/10.1126/sciimmunol.abg0833 |
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