#Interplay between #SARS-CoV-2 and the type I #interferon response (PLOS Pathog., abstract)

[Source: PLOS Pathogens, full page: (LINK). Abstract, edited.]

OPEN ACCESS | REVIEW

Interplay between SARS-CoV-2 and the type I interferon response

Margarida Sa Ribero, Nolwenn Jouvenet , Marlène Dreux , Sébastien Nisole

Published: July 29, 2020 | DOI: https://doi.org/10.1371/journal.ppat.1008737

 

Abstract

The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is responsible for the current COVID-19 pandemic. An unbalanced immune response, characterized by a weak production of type I interferons (IFN-Is) and an exacerbated release of proinflammatory cytokines, contributes to the severe forms of the disease. SARS-CoV-2 is genetically related to SARS-CoV and Middle East respiratory syndrome-related coronavirus (MERS-CoV), which caused outbreaks in 2003 and 2013, respectively. Although IFN treatment gave some encouraging results against SARS-CoV and MERS-CoV in animal models, its potential as a therapeutic against COVID-19 awaits validation. Here, we describe our current knowledge of the complex interplay between SARS-CoV-2 infection and the IFN system, highlighting some of the gaps that need to be filled for a better understanding of the underlying molecular mechanisms. In addition to the conserved IFN evasion strategies that are likely shared with SARS-CoV and MERS-CoV, novel counteraction mechanisms are being discovered in SARS-CoV-2–infected cells. Since the last coronavirus epidemic, we have made considerable progress in understanding the IFN-I response, including its spatiotemporal regulation and the prominent role of plasmacytoid dendritic cells (pDCs), which are the main IFN-I–producing cells. While awaiting the results of the many clinical trials that are evaluating the efficacy of IFN-I alone or in combination with antiviral molecules, we discuss the potential benefits of a well-timed IFN-I treatment and propose strategies to boost pDC-mediated IFN responses during the early stages of viral infection.

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Citation: Sa Ribero M, Jouvenet N, Dreux M, Nisole S (2020) Interplay between SARS-CoV-2 and the type I interferon response. PLoS Pathog 16(7): e1008737. https://doi.org/10.1371/journal.ppat.1008737

Editor: Kenneth Stapleford, NYU Langone Health, UNITED STATES

Published: July 29, 2020

Copyright: © 2020 Sa Ribero et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Funding: Research in the laboratory of NJ is funded by the CNRS, the Institut Pasteur, the European Molecular Biology Organisation (EMBO) Young Investigator Program, and the Agence Nationale de la Recherche Scientifique (ANR 16 CE15 0025 01 VIRO-STORM). Research related to the topic of this review in the team led by MD is supported by the Agence Nationale de la Recherche (ANR Flash COVID-19 and ANR 19-CE15-0025-01 JCJC iSYN). Research related to the topic of this review in the team led by SN is supported by the Labex EpiGenMed, an Investissements d’avenir program (ANR-10-LABX-12-01), the Région Occitanie and the Agence Nationale de la Recherche (ANR Flash COVID-19). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing interests: The authors have declared that no competing interests exist.

Keywords: SARS-CoV-2; COVID-19; Interferons.

——

Presence of #Genetic #Variants Among Young #Men With #Severe #COVID19 (JAMA, abstract)

[Source: JAMA, full page: (LINK). Abstract, edited.]

Presence of Genetic Variants Among Young Men With Severe COVID-19

Caspar I. van der Made, MD1,2,3,4; Annet Simons, PhD1; Janneke Schuurs-Hoeijmakers, MD, PhD1; Guus van den Heuvel, MD5; Tuomo Mantere, PhD1; Simone Kersten, MSc1,2,3; Rosanne C. van Deuren, MSc1,2,3; Marloes Steehouwer, BSc1; Simon V. van Reijmersdal, BSc1; Martin Jaeger, PhD2,3; Tom Hofste, BSc1; Galuh Astuti, PhD1; Jordi Corominas Galbany, PhD1; Vyne van der Schoot, MD, PhD6; Hans van der Hoeven, MD, PhD7; Wanda Hagmolen of ten Have, MD, PhD5; Eva Klijn, MD, PhD8; Catrien van den Meer, MD9; Jeroen Fiddelaers, MD10; Quirijn de Mast, MD, PhD2,3,4; Chantal P. Bleeker-Rovers, MD, PhD2,4,11; Leo A. B. Joosten, PhD2,3,4; Helger G. Yntema, PhD1,12; Christian Gilissen, PhD1,3; Marcel Nelen, PhD1; Jos W. M. van der Meer, MD, PhD2,3,4; Han G. Brunner, MD, PhD1,6,12,13; Mihai G. Netea, MD, PhD2,3,4,14; Frank L. van de Veerdonk, MD, PhD2,3,4; Alexander Hoischen, PhD1,2,3,4

Author Affiliations: 1 Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands; 2 Radboud University Medical Center Center for Infectious Diseases (RCI), Department of Internal Medicine, Radboud University Medical Center, Nijmegen, the Netherlands; 3 Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, the Netherlands; 4 Radboud Expertise Center for Immunodeficiency and Autoinflammation and Radboud Center for Infectious Disease (RCI), Radboud University Medical Center, Nijmegen, the Netherlands; 5 Pulmonology Department, Radboud University Medical Center, Nijmegen, the Netherlands; 6 Department of Clinical Genetics, Maastricht University Medical Center, Maastricht, the Netherlands; 7 Department of Intensive Care, Radboud University Medical Center Center for Infectious Diseases (RCI), Radboud University Medical Center, Nijmegen, the Netherlands; 8 Department of Intensive Care, Erasmus Medical Center, Rotterdam, the Netherlands; 9 Department of Intensive Care, Ziekenhuis Rivierenland, Tiel, the Netherlands; 10 Department of Pulmonology, Admiraal de Ruyter Ziekenhuis, Goes, the Netherlands; 11 Radboud Institute Health Sciences, Radboud University Medical Center, Nijmegen, the Netherlands; 12 Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, the Netherlands; 13 GROW School of Oncology and developmental biology, and MHeNs School of Mental Health and Neuroscience, Maastricht University, the Netherlands; 14 Immunology and Metabolism, Life and Medical Sciences Institute (LIMES), University of Bonn, Bonn, Germany

JAMA. Published online July 24, 2020. doi:10.1001/jama.2020.13719

 

Key Points

  • Question  – Are genetic variants associated with severe coronavirus disease 2019 (COVID-19) in young male patients?
  • Findings  – In a case series that included 4 young male patients with severe COVID-19 from 2 families, rare loss-of-function variants of the X-chromosomal TLR7 were identified, with immunological defects in type I and II interferon production.
  • Meaning  – These findings provide insights into the pathogenesis of COVID-19.

 

Abstract

Importance  

Severe coronavirus disease 2019 (COVID-19) can occur in younger, predominantly male, patients without preexisting medical conditions. Some individuals may have primary immunodeficiencies that predispose to severe infections caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

Objective  

To explore the presence of genetic variants associated with primary immunodeficiencies among young patients with COVID-19.

Design, Setting, and Participants  

Case series of pairs of brothers without medical history meeting the selection criteria of young (age <35 years) brother pairs admitted to the intensive care unit (ICU) due to severe COVID-19. Four men from 2 unrelated families were admitted to the ICUs of 4 hospitals in the Netherlands between March 23 and April 12, 2020. The final date of follow-up was May 16, 2020. Available family members were included for genetic variant segregation analysis and as controls for functional experiments.

Exposure  

Severe COVID-19.

Main Outcome and Measures  

Results of rapid clinical whole-exome sequencing, performed to identify a potential monogenic cause. Subsequently, basic genetic and immunological tests were performed in primary immune cells isolated from the patients and family members to characterize any immune defects.

Results  

The 4 male patients had a mean age of 26 years (range, 21-32), with no history of major chronic disease. They were previously well before developing respiratory insufficiency due to severe COVID-19, requiring mechanical ventilation in the ICU. The mean duration of ventilatory support was 10 days (range, 9-11); the mean duration of ICU stay was 13 days (range, 10-16). One patient died. Rapid clinical whole-exome sequencing of the patients and segregation in available family members identified loss-of-function variants of the X-chromosomal TLR7. In members of family 1, a maternally inherited 4-nucleotide deletion was identified (c.2129_2132del; p.[Gln710Argfs*18]); the affected members of family 2 carried a missense variant (c.2383G>T; p.[Val795Phe]). In primary peripheral blood mononuclear cells from the patients, downstream type I interferon (IFN) signaling was transcriptionally downregulated, as measured by significantly decreased mRNA expression of IRF7, IFNB1, and ISG15 on stimulation with the TLR7 agonist imiquimod as compared with family members and controls. The production of IFN-γ, a type II IFN, was decreased in patients in response to stimulation with imiquimod.

Conclusions and Relevance  

In this case series of 4 young male patients with severe COVID-19, rare putative loss-of-function variants of X-chromosomal TLR7 were identified that were associated with impaired type I and II IFN responses. These preliminary findings provide insights into the pathogenesis of COVID-19.

Keywords: SARS-CoV-2; COVID-19; Genetics; Immunodeficiency; Viral pathogenesis; Interferons.

——

Type I and Type III #IFN Restrict #SARS-CoV-2 Infection of Human #Airway #Epithelial Cultures (J Virol., abstract)

[Source: Journal of Virology, full page: (LINK). Abstract, edited.]

Type I and Type III IFN Restrict SARS-CoV-2 Infection of Human Airway Epithelial Cultures

Abigail Vanderheiden, Philipp Ralfs, Tatiana Chirkova, Amit A. Upadhyay, Matthew G. Zimmerman, Shamika Bedoya, Hadj Aoued, Gregory M. Tharp, Kathryn L. Pellegrini, Candela Manfredi, Eric Sorscher, Bernardo Mainou, Jenna L. Lobby, Jacob E. Kohlmeier, Anice C. Lowen, Pei-Yong Shi, Vineet D. Menachery, Larry J. Anderson, Arash Grakoui, Steven E. Bosinger, Mehul S. Suthar

DOI: 10.1128/JVI.00985-20

 

ABSTRACT

The newly emerged human coronavirus, SARS-CoV-2, has caused a pandemic of respiratory illness. Current evidence suggests that severe cases of SARS-CoV-2 are associated with a dysregulated immune response. However, little is known about how the innate immune system responds to SARS-CoV-2. Here, we modeled SARS-CoV-2 infection using primary human airway epithelial (pHAE) cultures, which are maintained in an air-liquid interface. We found that SARS-CoV-2 infects and replicates in pHAE cultures and is directionally released on the apical, but not basolateral surface. Transcriptional profiling studies found that infected pHAE cultures had a molecular signature dominated by pro-inflammatory cytokines and chemokine induction, including IL-6, TNFα, CXCL8, and identified NF-κB and ATF-4 as key drivers of this pro-inflammatory cytokine response. Surprisingly, we observed a complete lack of a type I or III interferon (IFN) response to SARS-CoV-2 infection. However, pre-treatment and post-treatment with type I and III IFNs significantly reduced virus replication in pHAE cultures that correlated with upregulation of antiviral effector genes. Combined, our findings demonstrate that SARS-CoV-2 does not trigger an IFN response but is sensitive to the effects of type I and III IFNs. Our studies demonstrate the utility of pHAE cultures to model SARS-CoV-2 infection and that both type I and III IFNs can serve as therapeutic options to treat COVID-19 patients.

 

IMPORTANCE

The current pandemic of respiratory illness, COVID-19, is caused by a recently emerged coronavirus named SARS-CoV-2. This virus infects airway and lung cells causing fever, dry cough, and shortness of breath. Severe cases of COVID-19 can result in lung damage, low blood oxygen levels, and even death. As there are currently no vaccines approved for use in humans, studies of the mechanisms of SARS-CoV-2 infection are urgently needed. Our research identifies an excellent system to model SARS-CoV-2 infection of the human airways, that can be used to test various treatments. Analysis of infection in this model system found that human airway epithelial cultures induce a strong pro-inflammatory cytokine response yet block the production of type I and III IFNs. to SARS-CoV-2. However, treatment of airway cultures with the immune molecules, type I or type III interferon (IFN) was able to inhibit SARS-CoV-2 infection. Thus, our model system identified type I or type III IFN as potential antiviral treatments for COVID-19 patients.

Copyright © 2020 American Society for Microbiology. All Rights Reserved.

This article is made available via the PMC Open Access Subset for unrestricted noncommercial re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.

Keywords: SARS-CoV-2; COVID-19; Viral pathogenesis; Interferons.

——

Retrospective Multicenter Cohort Study Shows Early #Interferon #Therapy Is Associated with Favorable #Clinical #Responses in #COVID19 Patients (Cell Host Microbe, abstract)

[Source: Cell Host and Microbe, full page: (LINK). Abstract, edited.]

Retrospective Multicenter Cohort Study Shows Early Interferon Therapy Is Associated with Favorable Clinical Responses in COVID-19 Patients

Nan Wang, Yan Zhan, Linyu Zhu, Zhibing Hou, Feng Liu, Pinhong Song, Feng Qiu, Xiaolin Wang, Xiafei Zou, Deyun Wan, Xiaosong Qian, Shanshan Wang, Yabi Guo, Hao Yu, Miao Cui, Gangling Tong, Yunsheng Xu, Zhihua Zheng, Yingying Lu, Peng Hong

Published: July 22, 2020 | DOI: https://doi.org/10.1016/j.chom.2020.07.005

 

Highlights

  • 242 of 446 analyzed COVID-19 patients received IFN-α2b, a type I IFN
  • Early initiation of IFN therapy was associated with reduced mortality
  • IFN therapy was not associated with recovery time for COVID-19
  • IFN-α2b was associated with better responses than were lopinavir/ritonavir

 

Summary

Interferons (IFNs) are widely used in treating coronavirus disease 2019 (COVID-19) patients. However, a recent report of ACE2, the host factor mediating SARS-Cov-2 infection, identifying it as interferon-stimulated raised considerable safety concern. To examine the association between the use and timing of IFN-α2b and clinical outcomes, we analyzed in a retrospective multicenter cohort study of 446 COVID-19 patients in Hubei, China. Regression models estimated that early administration (≤5 days after admission) of IFN-α2b was associated with reduced in-hospital mortality in comparison with no admission of IFN-α2b, whereas late administration of IFN-α2b was associated with increased mortality. Among survivors, early IFN-α2b was not associated with hospital discharge or computed tomography (CT) scan improvement, whereas late IFN-α2b was associated with delayed recovery. Additionally, early IFN-α2b and umifenovir alone or together were associated with reduced mortality and accelerated recovery in comparison with treatment with lopinavir/ritonavir (LPV/r) alone. We concluded that administration of IFN-α2b during the early stage of COVID-19 could induce favorable clinical responses.

Keywords: SARS-CoV-2; COVID-19; Antivirals; Interferons; Arbidol.

——

#Efficacy and #safety of #interferon β-1a in #treatment of #severe #COVID19: A #RCT (Antimicrob Agents Chemother., abstract)

[Source: Antimicrobial Agents and Chemotherapy, full page: (LINK). Abstract, edited.]

Efficacy and safety of interferon β-1a in treatment of severe COVID-19: A randomized clinical trial

Effat Davoudi-Monfared, Hamid Rahmani, Hossein Khalili, Mahboubeh  Hajiabdolbaghi, Mohamadreza Salehi, Ladan Abbasian, Hossein Kazemzadeh, Mir Saeed Yekaninejad

DOI: 10.1128/AAC.01061-20

 

ABSTRACT

Objectives:

To the best of our knowledge, there is no published study regarding use of IFN β-1a in the treatment of severe COVID-19. In this randomized clinical trial efficacy and safety of IFN β-1a has been evaluated in patients with severe COVID-19.

Methods:

Forty-two patients in the interferon group received IFN β-1a in addition to the national protocol medications (hydroxychloroquine plus lopinavir/ritonavir or atazanavir/ritonavir). Each 44 micrograms/ml (12 million IU/ml) of interferon β-1a was subcutaneously injected three times weekly for two consecutive weeks. The control group consisted 39 patients that received only the national protocol medications. Primary outcome of study was time to reach clinical response. Secondary outcomes were duration of hospital stay, length of ICU stay, 28-day mortality, effect of early or late administration of IFN on mortality, adverse effects and complications during the hospitalization.

Results:

Between 29th February to 3rd April 2020, 92 patients were recruited that finally 42 patients in the IFN group and 39 patients in the control group completed the study. As primary outcome, time to the clinical response was not significantly different between the IFN and the control groups (9.7 ± 5.8 vs. 8.3 ± 4.9 days respectively, P=0.95). On day 14, 66.7% vs. 43.6% of patients in the IFN group and the control group were discharged, respectively (OR= 2.5; 95% CI: 1.05- 6.37). The 28-day overall mortality was significantly lower in the IFN than the control group (19% vs. 43.6% respectively, p= 0.015). Early administration significantly reduced mortality (OR=13.5; 95% CI: 1.5-118).

Conclusion:

Although IFN did not change time to reach the clinical response, adding it to the national protocol significantly increased discharge rate on day 14 and decreased 28-day mortality.

Copyright © 2020 American Society for Microbiology. All Rights Reserved.

Keywords: SARS-CoV-2; COVID-19; Antivirals; Interferons.

——

#Efficacy and #safety of #interferon β-1a in #treatment of #severe #COVID-19: A #RCT (Antimicrob Agents Chemother., abstract)

[Source: Antimicrobial Agents and Chemotherapy, full page: (LINK). Abstract, edited.]

Efficacy and safety of interferon β-1a in treatment of severe COVID-19: A randomized clinical trial

Effat Davoudi-Monfared, Hamid Rahmani, Hossein Khalili, Mahboubeh  Hajiabdolbaghi, Mohamadreza Salehi, Ladan Abbasian, Hossein Kazemzadeh, Mir Saeed Yekaninejad

DOI: 10.1128/AAC.01061-20

 

ABSTRACT

Objectives:

To the best of our knowledge, there is no published study regarding use of IFN β-1a in the treatment of severe COVID-19. In this randomized clinical trial efficacy and safety of IFN β-1a has been evaluated in patients with severe COVID-19.

Methods:

Forty-two patients in the interferon group received IFN β-1a in addition to the national protocol medications (hydroxychloroquine plus lopinavir/ritonavir or atazanavir/ritonavir). Each 44 micrograms/ml (12 million IU/ml) of interferon β-1a was subcutaneously injected three times weekly for two consecutive weeks. The control group consisted 39 patients that received only the national protocol medications. Primary outcome of study was time to reach clinical response. Secondary outcomes were duration of hospital stay, length of ICU stay, 28-day mortality, effect of early or late administration of IFN on mortality, adverse effects and complications during the hospitalization.

Results:

Between 29th February to 3rd April 2020, 92 patients were recruited that finally 42 patients in the IFN group and 39 patients in the control group completed the study. As primary outcome, time to the clinical response was not significantly different between the IFN and the control groups (9.7 ± 5.8 vs. 8.3 ± 4.9 days respectively, P=0.95). On day 14, 66.7% vs. 43.6% of patients in the IFN group and the control group were discharged, respectively (OR= 2.5; 95% CI: 1.05- 6.37). The 28-day overall mortality was significantly lower in the IFN than the control group (19% vs. 43.6% respectively, p= 0.015). Early administration significantly reduced mortality (OR=13.5; 95% CI: 1.5-118).

Conclusion:

Although IFN did not change time to reach the clinical response, adding it to the national protocol significantly increased discharge rate on day 14 and decreased 28-day mortality.

Copyright © 2020 American Society for Microbiology. All Rights Reserved.

Keywords: SARS-CoV-2; COVID-19; Interferons.

——

Impaired type I #interferon #activity and #inflammatory responses in #severe #COVID19 patients (Science, abstract)

[Source: Science, full page: (LINK). Abstract, edited.]

Impaired type I interferon activity and inflammatory responses in severe COVID-19 patients

Jérôme Hadjadj1,2,*, Nader Yatim2,3,*, Laura Barnabei1, Aurélien Corneau4, Jeremy Boussier3, Nikaïa Smith3, Hélène Péré5,6, Bruno Charbit7, Vincent Bondet3, Camille Chenevier-Gobeaux8, Paul Breillat2, Nicolas Carlier9, Rémy Gauzit10, Caroline Morbieu2, Frédéric Pène11, Nathalie Marin11, Nicolas Roche9, Tali-Anne Szwebel2, Sarah H Merkling12, Jean-Marc Treluyer13, David Veyer5, Luc Mouthon2, Catherine Blanc4, Pierre-Louis Tharaux6, Flore Rozenberg14, Alain Fischer1,15,16, Darragh Duffy3,7,†, Frédéric Rieux-Laucat1,†, Solen Kernéis10,17,†, Benjamin Terrier2,6,†,‡

1 Imagine institute, laboratory of Immunogenetics of Pediatric Autoimmune Diseases, INSERM UMR 1163, Université de Paris, F-75015, Paris. 2 Department of Internal Medicine, National Referral Center for Rare Systemic Autoimmune Diseases, Assistance Publique Hôpitaux de Paris-Centre (APHP-CUP), Université de Paris, F-75014, Paris. 3 Laboratory of Dendritic Cell Immunobiology, Inserm U1223, Department of Immunology, Institut Pasteur, F-75015, Paris. 4 Sorbonne Université, Faculté de médecine, UMS037, PASS, Plateforme de cytométrie de la Pitié-Salpêtrière CyPS, F-75013, Paris. 5 Department of Virology, APHP-CUP, Université de Paris, F-75015, Paris. 6 PARCC, INSERM U970, Paris. 7 Cytometry and Biomarkers UTechS, CRT, Institut Pasteur, F-75015, Paris. 8 Department of Automated Diagnostic Biology, APHP-CUP, F-75014, Paris. 9 Department of Pulmonology, APHP-CUP, Institut Cochin, UMR 1016, Université de Paris, F-75014, Paris. 10 Equipe Mobile d’Infectiologie, APHP-CUP, Université de Paris, F-75014, Paris. 11 Medical intensive care unit, APHP-CUP, Institut Cochin, INSERM U1016, CNRS UMR 8104, Université de Paris, F-75014, Paris. 12 Insect-Virus Interactions Unit, Institut Pasteur, UMR2000, CNRS, Paris. 13 Centre Régional de Pharmacovigilance, APHP-CUP, Université de Paris, F-75014, Paris. 14 Department of Virology, APHP-CUP, Université de Paris, F-75014, Paris. 15 Unité d’immunologie hématologie et rhumatologie pédiatriques, APHP-CUP, Université de Paris, F-75015, Paris. 16 Collège de France, Paris. 17 Epidémiologie et modélisation de la résistance aux antimicrobiens, Institut Pasteur, F-75015, Paris, France.

‡Corresponding author. E-mail: benjamin.terrier@aphp.fr

* These authors contributed equally to this work.

† These authors contributed equally to this work.

Science  13 Jul 2020: eabc6027 | DOI: 10.1126/science.abc6027

 

Abstract

Coronavirus disease 2019 (COVID-19) is characterized by distinct patterns of disease progression suggesting diverse host immune responses. We performed an integrated immune analysis on a cohort of 50 COVID-19 patients with various disease severity. A unique phenotype was observed in severe and critical patients, consisting of a highly impaired interferon (IFN) type I response (characterized by no IFN-β and low IFN-α production and activity), associated with a persistent blood viral load and an exacerbated inflammatory response. Inflammation was partially driven by the transcriptional factor NF-κB and characterized by increased tumor necrosis factor (TNF)-α and interleukin (IL)-6 production and signaling. These data suggest that type-I IFN deficiency in the blood could be a hallmark of severe COVID-19 and provide a rationale for combined therapeutic approaches.

Keywords: SARS-CoV-2; COVID-19; Interferons; Immunopathology.

——

#SARS‐CoV‐2‐reactive #interferon‐γ‐producing #CD8+ T cells in patients hospitalized with #Coronavirus Disease 2019 (J Med Virol., abstract)

[Source: Journal of Medical Virology, full page: (LINK). Abstract, edited.]

SARS‐CoV‐2‐reactive interferon‐γ‐producing CD8+ T cells in patients hospitalized with Coronavirus Disease 2019

Estela Giménez,  Eliseo Albert,  Ignacio Torres,  María José Remigia,  María Jesús Alcaraz, María José Galindo,  María Luisa Blasco,  Carlos Solano,  María José Forner,  Josep Redón, Jaime Signes‐Costa,  David Navarro …

First published: 24 June 2020 | DOI:  https://doi.org/10.1002/jmv.26213

This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1002/jmv.26213

 

ABSTRACT

There is limited information on SARS‐CoV‐2 T‐cell immune responses in patients with COVID‐19. Both CD4+ and CD8+ T cells may be instrumental in resolution of and protection from SARS‐CoV‐2 infection. Here, we tested 25 hospitalized patients either with microbiologically documented COVID‐19 (n=19) or highly suspected of having the disease (n=6) for presence of SARS‐CoV‐2‐reactive CD69+‐expressing interferon‐γ (IFN‐γ) producing CD8+ T cells using flow‐cytometry for intracellular cytokine staining assay. Two sets of overlapping peptides encompassing the SARS‐CoV‐2 Spike glycoprotein N‐terminal 1‐643 amino acid sequence and the entire sequence of SARS‐CoV‐2 M protein were used simultaneously as antigenic stimulus. Ten patients (40%) had detectable responses, displaying frequencies ranging from 0.15 to 2.7% (median of 0.57 cells/µL; range, 0.43‐9.98 cells/µL). The detection rate of SARS‐CoV‐2‐reactive IFN‐γ CD8+ T cells in patients admitted to intensive care was comparable (P =0.28) to the rate in patients hospitalized in other medical wards. No correlation was found between SARS‐CoV‐2‐reactive IFN‐γ CD8+ T‐cell counts and SARS‐CoV‐2 S‐specific antibody levels. Likewise, no correlation was observed between either SARS‐CoV‐2‐reactive IFN‐γ CD8+ T cells or S‐specific IgG‐antibody titers and blood cell count or levels of inflammatory biomarkers. In summary, in this descriptive, preliminary study we showed that SARS‐CoV‐2‐reactive IFN‐γ CD8+ T cells can be detected in a non‐negligible percentage of patients with moderate to severe forms of COVID‐19. Further studies are warranted to determine whether quantitation of these T‐cell subsets may provide prognostic information on the clinical course of COVID‐19.

This article is protected by copyright. All rights reserved.

Keywords: SARS-CoV-2; COVID-19; Interferons; Immunopathology; Immunology.

——

Critical role of type III #interferon in controlling #SARS-CoV-2 infection in #human #intestinal epithelial cells (Cell Rep., abstract)

[Source: Cell Reports, full page: (LINK). Abstract, edited.]

Critical role of type III interferon in controlling SARS-CoV-2 infection in human intestinal epithelial cells

Megan L. Stanifer, Carmon Kee, Mirko Cortese, Camila Metz Zumaran, Sergio Triana, Markus Mukenhirn, Hans-Georg Kraeusslich, Theodore Alexandrov, Ralf Bartenschlager, Steeve Boulant

Open Access | Published: June 19, 2020 | DOI: https://doi.org/10.1016/j.celrep.2020.107863

 

Highlights

  • Human intestinal epithelium cells (hIECs) can be infected by SARS-CoV-2
  • hIECs support SARS-CoV-2 replication and produce de-novo viruses
  • SARS-CoV-2 infection can be controlled in hIECs by type I and III interferon

 

Summary

SARS-CoV-2 is an unprecedented worldwide health problem that requires concerted and global approaches to stop the COVID-19 pandemic. Although SARS-CoV-2 primarily targets lung epithelium cells, there is growing evidence that the intestinal epithelium is also infected. Here, using both colon-derived cell lines and primary non-transformed colon organoids, we engage in the first comprehensive analysis of SARS-CoV-2 lifecycle in human intestinal epithelial cells (hIECs). Our results demonstrate that hIECs fully support SARS-CoV-2 infection, replication and production of infectious de-novo virus particles. We found that viral infection elicited an extremely robust intrinsic immune response where interferon-mediated responses were efficient at controlling SARS-CoV-2 replication and de-novo virus production. Taken together, our data demonstrate that hIECs are a productive site of SARS-CoV-2 replication and suggest that the enteric phase of SARS-CoV-2 may participate in the pathologies observed in COVID-19 patients by contributing in increasing patient viremia and by fueling an exacerbated cytokine response.

Accepted: June 15, 2020 – Received in revised form: May 18, 2020 – Received: April 22, 2020

Publication stage In Press Accepted Manuscript

Identification DOI: https://doi.org/10.1016/j.celrep.2020.107863

Copyright © 2020

Keywords: SARS-CoV-2; COVID-19; Interferons; Viral pathogenesis.

——

Attenuated #interferon and pro-inflammatory response in #SARS-CoV-2-infected human #dendritic cells is associated with viral #antagonism of #STAT1 phosphorylation (J Infect Dis., abstract)

[Source: Journal of Infectious Diseases, full page: (LINK). Abstract, edited.]

Attenuated interferon and pro-inflammatory response in SARS-CoV-2-infected human dendritic cells is associated with viral antagonism of STAT1 phosphorylation

Dong Yang, Hin Chu, Yuxin Hou, Yue Chai, Huiping Shuai, Andrew Chak-Yiu Lee, Xi Zhang, Yixin Wang, Bingjie Hu, Xiner Huang, Terrence Tsz-Tai Yuen, Jian-Piao Cai, Jie Zhou, Shuofeng Yuan, Anna Jinxia Zhang, Jasper Fuk-Woo Chan, Kwok-Yung Yuen

The Journal of Infectious Diseases, jiaa356, https://doi.org/10.1093/infdis/jiaa356

Published: 21 June 2020

 

ABSTRACT

Clinical manifestations of COVID-19 vary from asymptomatic virus shedding, non-specific pharyngitis, to pneumonia with silent hypoxia and respiratory failure. Dendritic cells and macrophages are sentinel cells for innate and adaptive immunity that affect the pathogenesis of SARS and MERS. However, the interplay between SARS-CoV-2 and these cell types remains unknown. Herein, we investigated the infection and host response of monocyte-derived dendritic cells (moDCs) and macrophages (MDMs) infected by SARS-CoV-2. We demonstrated that moDCs and MDMs were permissive to SARS-CoV-2 infection and protein expression but did not support productive virus replication. Importantly, SARS-CoV-2 launched an attenuated interferon response in both cell types. Additionally, SARS-CoV-2 triggered significant pro-inflammatory cytokine/chemokine expression in MDMs but not in moDCs. Further investigations suggested that this attenuated immune response to SARS-CoV-2 in moDCs was associated with viral antagonism of STAT1 phosphorylation. These findings on pathogenesis may explain the mild and insidious course of COVID-19 till late deterioration.

COVID-19, SARS-CoV-2, coronavirus, dendritic cells, macrophages, moDCs, MDMs

Issue Section: Major Article

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Keywords: SARS-CoV-2; COVID-19; Cytokines; Interferons; Immunopathology; Viral pathogenesis.

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