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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...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Association for the Advancement of Science 2021
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.
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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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