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Functional Exhaustion of Type I and II Interferons Production in Severe COVID-19 Patients

Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has emerged in Wuhan in December 2019 and has since spread across the world. Even though the majority of patients remain completely asymptomatic, some develop severe systemic complications. In...

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Autores principales: Ruetsch, Caroline, Brglez, Vesna, Crémoni, Marion, Zorzi, Kévin, Fernandez, Céline, Boyer-Suavet, Sonia, Benzaken, Sylvia, Demonchy, Elisa, Risso, Karine, Courjon, Johan, Cua, Eric, Ichai, Carole, Dellamonica, Jean, Passeron, Thierry, Seitz-Polski, Barbara
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7873370/
https://www.ncbi.nlm.nih.gov/pubmed/33585507
http://dx.doi.org/10.3389/fmed.2020.603961
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author Ruetsch, Caroline
Brglez, Vesna
Crémoni, Marion
Zorzi, Kévin
Fernandez, Céline
Boyer-Suavet, Sonia
Benzaken, Sylvia
Demonchy, Elisa
Risso, Karine
Courjon, Johan
Cua, Eric
Ichai, Carole
Dellamonica, Jean
Passeron, Thierry
Seitz-Polski, Barbara
author_facet Ruetsch, Caroline
Brglez, Vesna
Crémoni, Marion
Zorzi, Kévin
Fernandez, Céline
Boyer-Suavet, Sonia
Benzaken, Sylvia
Demonchy, Elisa
Risso, Karine
Courjon, Johan
Cua, Eric
Ichai, Carole
Dellamonica, Jean
Passeron, Thierry
Seitz-Polski, Barbara
author_sort Ruetsch, Caroline
collection PubMed
description Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has emerged in Wuhan in December 2019 and has since spread across the world. Even though the majority of patients remain completely asymptomatic, some develop severe systemic complications. In this prospective study we compared the immunological profile of 101 COVID-19 patients with either mild, moderate or severe form of the disease according to the WHO classification, as well as of 50 healthy subjects, in order to identify functional immune factors independently associated with severe forms of COVID-19. Plasma cytokine levels, and cytokine levels upon in vitro non-specific stimulation of innate and adaptive immune cells, were measured at several time points during the course of the disease. As described previously, inflammatory cytokines IL1β, IL6, IL8, and TNFα associated with cytokine storm were significantly increased in the plasma of moderate and severe COVID-19 patients (p < 0.0001 for all cytokines). During follow-up, plasma IL6 levels decreased between the moment of admission to the hospital and at the last observation carried forward for patients with favorable outcome (p = 0.02148). After in vitro stimulation of immune cells from COVID-19 patients, reduced levels of both type I and type II interferons (IFNs) upon in vitro stimulation were correlated with increased disease severity [type I IFN (IFNα): p > 0.0001 mild vs. moderate and severe; type II IFN (IFNγ): p = 0.0002 mild vs. moderate and p < 0.0001 mild vs. severe] suggesting a functional exhaustion of IFNs production. Stimulated IFNα levels lower than 2.1 pg/ml and IFNγ levels lower than 15 IU/mL at admission to the hospital were associated with more complications during hospitalization (p = 0.0098 and p =0.0002, respectively). A low IFNγ level was also confirmed by multivariable analysis [p = 0.0349 OR = 0.98 (0.962; 0.999)] as an independent factor of complications. In vitro treatment with type IFNα restored type IFNγ secretion in COVID-19 patients while the secretion of pro-inflammatory cytokines IL6 and IL1β remained stable or decreased, respectively. These results (a) demonstrate a functional exhaustion of both innate and adaptive immune response in severe forms of COVID-19; (b) identify IFNα and IFNγ as new potential biomarkers of severity; and (c) highlight the importance of targeting IFNs when considering COVID-19 treatment in order to re-establish a normal balance between inflammatory and Th1 effector cytokines.
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spelling pubmed-78733702021-02-11 Functional Exhaustion of Type I and II Interferons Production in Severe COVID-19 Patients Ruetsch, Caroline Brglez, Vesna Crémoni, Marion Zorzi, Kévin Fernandez, Céline Boyer-Suavet, Sonia Benzaken, Sylvia Demonchy, Elisa Risso, Karine Courjon, Johan Cua, Eric Ichai, Carole Dellamonica, Jean Passeron, Thierry Seitz-Polski, Barbara Front Med (Lausanne) Medicine Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has emerged in Wuhan in December 2019 and has since spread across the world. Even though the majority of patients remain completely asymptomatic, some develop severe systemic complications. In this prospective study we compared the immunological profile of 101 COVID-19 patients with either mild, moderate or severe form of the disease according to the WHO classification, as well as of 50 healthy subjects, in order to identify functional immune factors independently associated with severe forms of COVID-19. Plasma cytokine levels, and cytokine levels upon in vitro non-specific stimulation of innate and adaptive immune cells, were measured at several time points during the course of the disease. As described previously, inflammatory cytokines IL1β, IL6, IL8, and TNFα associated with cytokine storm were significantly increased in the plasma of moderate and severe COVID-19 patients (p < 0.0001 for all cytokines). During follow-up, plasma IL6 levels decreased between the moment of admission to the hospital and at the last observation carried forward for patients with favorable outcome (p = 0.02148). After in vitro stimulation of immune cells from COVID-19 patients, reduced levels of both type I and type II interferons (IFNs) upon in vitro stimulation were correlated with increased disease severity [type I IFN (IFNα): p > 0.0001 mild vs. moderate and severe; type II IFN (IFNγ): p = 0.0002 mild vs. moderate and p < 0.0001 mild vs. severe] suggesting a functional exhaustion of IFNs production. Stimulated IFNα levels lower than 2.1 pg/ml and IFNγ levels lower than 15 IU/mL at admission to the hospital were associated with more complications during hospitalization (p = 0.0098 and p =0.0002, respectively). A low IFNγ level was also confirmed by multivariable analysis [p = 0.0349 OR = 0.98 (0.962; 0.999)] as an independent factor of complications. In vitro treatment with type IFNα restored type IFNγ secretion in COVID-19 patients while the secretion of pro-inflammatory cytokines IL6 and IL1β remained stable or decreased, respectively. These results (a) demonstrate a functional exhaustion of both innate and adaptive immune response in severe forms of COVID-19; (b) identify IFNα and IFNγ as new potential biomarkers of severity; and (c) highlight the importance of targeting IFNs when considering COVID-19 treatment in order to re-establish a normal balance between inflammatory and Th1 effector cytokines. Frontiers Media S.A. 2021-01-27 /pmc/articles/PMC7873370/ /pubmed/33585507 http://dx.doi.org/10.3389/fmed.2020.603961 Text en Copyright © 2021 Ruetsch, Brglez, Crémoni, Zorzi, Fernandez, Boyer-Suavet, Benzaken, Demonchy, Risso, Courjon, Cua, Ichai, Dellamonica, Passeron and Seitz-Polski. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Medicine
Ruetsch, Caroline
Brglez, Vesna
Crémoni, Marion
Zorzi, Kévin
Fernandez, Céline
Boyer-Suavet, Sonia
Benzaken, Sylvia
Demonchy, Elisa
Risso, Karine
Courjon, Johan
Cua, Eric
Ichai, Carole
Dellamonica, Jean
Passeron, Thierry
Seitz-Polski, Barbara
Functional Exhaustion of Type I and II Interferons Production in Severe COVID-19 Patients
title Functional Exhaustion of Type I and II Interferons Production in Severe COVID-19 Patients
title_full Functional Exhaustion of Type I and II Interferons Production in Severe COVID-19 Patients
title_fullStr Functional Exhaustion of Type I and II Interferons Production in Severe COVID-19 Patients
title_full_unstemmed Functional Exhaustion of Type I and II Interferons Production in Severe COVID-19 Patients
title_short Functional Exhaustion of Type I and II Interferons Production in Severe COVID-19 Patients
title_sort functional exhaustion of type i and ii interferons production in severe covid-19 patients
topic Medicine
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7873370/
https://www.ncbi.nlm.nih.gov/pubmed/33585507
http://dx.doi.org/10.3389/fmed.2020.603961
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