Potential #influence of #COVID19 / #ACE2 on the #female #reproductive system (Mol Human Reprod., abstract)

[Source: Molecular Human Reproduction, full page: (LINK). Abstract, edited.]

Potential influence of COVID-19/ACE2 on the female reproductive system

Yan Jing, Li Run-Qian, Wang Hao-Ran, Chen Hao-Ran, Liu Ya-Bin, Gao Yang, Chen Fei

Molecular Human Reproduction, gaaa030, https://doi.org/10.1093/molehr/gaaa030

Published: 04 May 2020



The 2019 novel coronavirus (2019-nCoV) appeared in December 2019 and then spread throughout the world rapidly. The virus invades the target cell by binding to angiotensin-converting enzyme (ACE) 2 and modulates the expression of ACE2 in host cells. ACE2, a pivotal component of the renin-angiotensin system, exerts its physiological functions by modulating the levels of angiotensin II (Ang II) and Ang-(1-7). We reviewed the literature that reported the distribution and function of ACE2 in the female reproductive system, hoping to clarify the potential harm of 2019-nCoV to female fertility. The available evidence suggests that ACE2 is widely expressed in the ovary, uterus, vagina and placenta. Therefore, we believe that apart from droplets and contact transmission, the possibility of mother-to-child and sexual transmission also exists. Ang II, ACE2 and Ang-(1-7) regulate follicle development and ovulation, modulate luteal angiogenesis and degeneration, and also influence the regular changes in endometrial tissue and embryo development. Taking these functions into account, 2019-nCoV may disturb the female reproductive functions through regulating ACE2.

2019-nCoV, COVID-19, angiotensin-converting enzyme 2, angiotensin II, Ang-(1-7), female reproductive system, breastfeeding, pregnancy, coronavirus

Issue Section: Review

This content is only available as a PDF.

© The Author(s) 2020. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved.

This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model)

Keywords: SARS-CoV-2; COVID-19; ACE2; Pregnancy; Viral pathogenesis.


#SARS-CoV-2 productively infects #human #gut #enterocytes (Science, abstract)

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

SARS-CoV-2 productively infects human gut enterocytes

Mart M. Lamers1,*, Joep Beumer2,*, Jelte van der Vaart2,*, Kèvin Knoops3, Jens Puschhof2, Tim I. Breugem1, Raimond B. G. Ravelli3, J. Paul van Schayck3, Anna Z. Mykytyn1, Hans Q. Duimel3, Elly van Donselaar3, Samra Riesebosch1, Helma J. H. Kuijpers3, Debby Schippers1, Willine J. van de Wetering3, Miranda de Graaf1, Marion Koopmans1, Edwin Cuppen4,5, Peter J. Peters3, Bart L. Haagmans1,†, Hans Clevers2,†,‡

1 Viroscience Department, Erasmus Medical Center, Rotterdam, Netherlands. 2 Oncode Institute, Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences and University Medical Center, Utrecht, Netherlands. 3 The Maastricht Multimodal Molecular Imaging Institute, Maastricht University, Maastricht, Netherlands. 4 Center for Molecular Medicine and Oncode Institute, University Medical Centre Utrecht, Utrecht, Netherlands. 5 Hartwig Medical Foundation, Amsterdam, Netherlands.

‡Corresponding author. Email: h.clevers@hubrecht.eu (H.C.); b.haagmans@erasmusmc.nl (B.L.H.)

* These authors contributed equally to this work.

† These authors contributed equally to this work.

Science  01 May 2020: eabc1669 | DOI: 10.1126/science.abc1669



The virus severe acute respiratory syndrome–coronavirus 2 (SARS-CoV-2) can cause coronavirus disease 2019 (COVID-19), an influenza-like disease that is primarily thought to infect the lungs with transmission via the respiratory route. However, clinical evidence suggests that the intestine may present another viral target organ. Indeed, the SARS-CoV-2 receptor angiotensin converting enzyme 2 (ACE2) is highly expressed on differentiated enterocytes. In human small intestinal organoids (hSIOs), enterocytes were readily infected by SARS-CoV and SARS-CoV-2 as demonstrated by confocal- and electron-microscopy. Consequently, significant titers of infectious viral particles were detected. mRNA expression analysis revealed strong induction of a generic viral response program. Hence, intestinal epithelium supports SARS-CoV-2 replication, and hSIOs serve as an experimental model for coronavirus infection and biology.

Keywords: SARS-CoV-2; COVID-19; ACE2; Viral pathogenesis.


Comparative #tropism, #replication kinetics, and cell #damage profiling of #SARS-CoV-2 and SARS-CoV with implications for clinical manifestations, transmissibility, and laboratory studies of COVID-19: an observational study (Lancet Microbe, abstract)

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

Comparative tropism, replication kinetics, and cell damage profiling of SARS-CoV-2 and SARS-CoV with implications for clinical manifestations, transmissibility, and laboratory studies of COVID-19: an observational study

Hin Chu, PhD †, Jasper Fuk-Woo Chan, MD †, Terrence Tsz-Tai Yuen, BA †, Huiping Shuai, PhD †, Shuofeng Yuan, PhD, Yixin Wang, MPhil, Bingjie Hu, MPhil, Cyril Chik-Yan Yip, PhD, Jessica Oi-Ling Tsang, BSc, Xiner Huang, BSc, Yue Chai, MPhil, Dong Yang, MPhil, Yuxin Hou, MPhil, Kenn Ka-Heng Chik, MMedSc, Xi Zhang, BSc, Agnes Yim-Fong Fung, BSc, Hoi-Wah Tsoi, MPhil, Jian-Piao Cai, BSc, Wan-Mui Chan, PhD, Jonathan Daniel Ip, MSc, Allen Wing-Ho Chu, MSc, Jie Zhou, PhD, David Christopher Lung, FRCPath, Kin-Hang Kok, PhD, Kelvin Kai-Wang To, MD, Owen Tak-Yin Tsang, FRCP, Kwok-Hung Chan, PhD, Prof Kwok-Yung Yuen, MD

Open Access | Published: April 21, 2020 | DOI: https://doi.org/10.1016/S2666-5247(20)30004-5




Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was reported from China in January, 2020. SARS-CoV-2 is efficiently transmitted from person to person and, in 2 months, has caused more than 82 000 laboratory-confirmed cases of coronavirus disease 2019 (COVID-19) and 2800 deaths in 46 countries. The total number of cases and deaths has surpassed that of the 2003 severe acute respiratory syndrome coronavirus (SARS-CoV). Although both COVID-19 and severe acute respiratory syndrome (SARS) manifest as pneumonia, COVID-19 is associated with apparently more efficient transmission, fewer cases of diarrhoea, increased mental confusion, and a lower crude fatality rate. However, the underlying virus–host interactive characteristics conferring these observations on transmissibility and clinical manifestations of COVID-19 remain unknown.


We systematically investigated the cellular susceptibility, species tropism, replication kinetics, and cell damage of SARS-CoV-2 and compared findings with those for SARS-CoV. We compared SARS-CoV-2 and SARS-CoV replication in different cell lines with one-way ANOVA. For the area under the curve comparison between SARS-CoV-2 and SARS-CoV replication in Calu3 (pulmonary) and Caco2 (intestinal) cells, we used Student’s t test. We analysed cell damage induced by SARS-CoV-2 and SARS-CoV with one-way ANOVA.


SARS-CoV-2 infected and replicated to comparable levels in human Caco2 cells and Calu3 cells over a period of 120 h (p=0·52). By contrast, SARS-CoV infected and replicated more efficiently in Caco2 cells than in Calu3 cells under the same multiplicity of infection (p=0·0098). SARS-CoV-2, but not SARS-CoV, replicated modestly in U251 (neuronal) cells (p=0·036). For animal species cell tropism, both SARS-CoV and SARS-CoV-2 replicated in non-human primate, cat, rabbit, and pig cells. SARS-CoV, but not SARS-CoV-2, infected and replicated in Rhinolophus sinicus bat kidney cells. SARS-CoV-2 consistently induced significantly delayed and milder levels of cell damage than did SARS-CoV in non-human primate cells (VeroE6, p=0·016; FRhK4, p=0·0004).


As far as we know, our study presents the first quantitative data for tropism, replication kinetics, and cell damage of SARS-CoV-2. These data provide novel insights into the lower incidence of diarrhoea, decreased disease severity, and reduced mortality in patients with COVID-19, with respect to the pathogenesis and high transmissibility of SARS-CoV-2 compared with SARS-CoV.


May Tam Mak Mei Yin, The Shaw Foundation Hong Kong, Richard Yu and Carol Yu, Michael Seak-Kan Tong, Respiratory Viral Research Foundation, Hui Ming, Hui Hoy and Chow Sin Lan Charity Fund, Chan Yin Chuen Memorial Charitable Foundation, Marina Man-Wai Lee, The Hong Kong Hainan Commercial Association South China Microbiology Research Fund, The Jessie & George Ho Charitable Foundation, Perfect Shape Medical, The Consultancy Service for Enhancing Laboratory Surveillance of Emerging Infectious Diseases and Research Capability on Antimicrobial Resistance for the Department of Health of the Hong Kong Special Administrative Region Government, The Theme-Based Research Scheme of the Research Grants Council, Sanming Project of Medicine in Shenzhen, and The High Level-Hospital Program, Health Commission of Guangdong Province, China.

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


#SARS-CoV-2 #receptor #ACE2 is an #interferon-stimulated #gene in #human #airway epithelial cells and is detected in specific cell subsets across tissues (Cell Press, abstract)

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

Journal pre-proof | DOI: 10.1016/j.cell.2020.04.035

This is a PDF file of an accepted peer-reviewed article but is not yet the definitive version  of record. This version will undergo additional copyediting, typesetting and  review before it is published in its final form, but we are providing this version to give  early visibility of the article. Please note that, during the production process, errors may  be discovered which could affect the content, and all legal disclaimers that apply to the  journal pertain.

© 2020 The Author(s).

SARS-CoV-2 receptor ACE2 is an interferon-stimulated gene in human airway epithelial  cells and is detected in specific cell subsets across tissues

Carly G. K. Ziegler1,2,3,4,5,6*, Samuel J. Allon2,4,5,7,*, Sarah K. Nyquist2,4,5,8,9,*, Ian M.  Mbano10,11,*, Vincent N. Miao1,2,4,5, Constantine N. Tzouanas1,2,4,5, Yuming Cao12,  Ashraf S. Yousif4, Julia Bals4, Blake M. Hauser4,13, Jared Feldman4,13,14, Christoph  Muus5,15, Marc H. Wadsworth II2,3,4,5,7, Samuel W. Kazer2,4,5,7, Travis K.  Hughes1,4,5,16, Benjamin Doran2,4,5,7,17,18, G. James Gatter2,4,5, Marko  Vukovic2,3,4,5,7, Faith Taliaferro5,18, Benjamin E. Mead2,3,4,5,7, Zhiru Guo12, Jennifer P.  Wang12, Delphine Gras19, Magali Plaisant20, Meshal Ansari21,22,23, Ilias  Angelidis21,22, Heiko Adler22,24, Jennifer M.S. Sucre25, Chase J. Taylor26, Brian Lin27,  Avinash Waghray27, Vanessa Mitsialis18,28, Daniel F. Dwyer29, Kathleen M. Buchheit29,  Joshua A. Boyce29, Nora A. Barrett29, Tanya M. Laidlaw29, Shaina L. Carroll30, Lucrezia  Colonna31, Victor Tkachev17,32,33, Christopher W. Peterson34,35, Alison Yu17,36,  Hengqi Betty Zheng36, Hannah P. Gideon37,38, Caylin G. Winchell37,38,39, Philana Ling  Lin38,40,41, Colin D. Bingle42, Scott B. Snapper18,28, Jonathan A. Kropski43,44,45, Fabian  J. Theis23, Herbert B. Schiller21,22, Laure-Emmanuelle Zaragosi20, Pascal  Barbry20 Alasdair Leslie10,46, Hans-Peter Kiem34,35, JoAnne L. Flynn37,38, Sarah M.  Fortune4,5,47, Bonnie Berger9,48, Robert W. Finberg12, Leslie S. Kean17,32,33, Manuel  Garber12, Aaron G. Schmidt4,13, Daniel Lingwood4, Alex K. Shalek1-8,16,33,49,#, Jose  Ordovas-Montanes5,16,18,49,#, HCA Lung Biological Network

*These authors contributed equally to this work

#These senior authors contributed equally to this work

Correspondence to: Alex K. Shalek shalek@mit.edu – Jose Ordovas-Montanes (lead  contact) jose.ordovas-montanes@childrens.harvard.edu – HCA Lung Biological Network lung-network@humancellatlas.org

Affiliations: 1Program in Health Sciences & Technology, Harvard Medical School &  Massachusetts Institute of Technology, Boston, MA 02115, USA; 2 Institute for Medical  Engineering & Science, Massachusetts Institute of Technology, Cambridge, MA 02142, USA; 3 Koch Institute for Integrative Cancer Research, Massachusetts Institute of  Technology, Cambridge, MA 02139, USA; 4 Ragon Institute of MGH, MIT, and Harvard,  Cambridge, MA 02139, USA; 5 Broad Institute of MIT and Harvard, Cambridge, MA 02142,  USA; 6 Harvard Graduate Program in Biophysics, Harvard University, Cambridge,  MA 02138, USA; 7 Department of Chemistry, Massachusetts Institute of Technology,  Cambridge, MA 02139, USA; 8 Program in Computational & Systems Biology,  Massachusetts Institute of Technology, Cambridge, MA 02139, USA; 9 Computer Science &  Artificial Intelligence Lab, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; 10 African Health Research Institute, Durban, South Africa; 11 School of  Laboratory Medicine and Medical Sciences, College of Health Sciences, University of  KwaZulu-Natal, Durban, South Africa; 12 University of Massachusetts Medical School,  Worcester, MA 01655, USA; 13 Department of Microbiology, Harvard Medical School,  Boston, MA 02115, USA; 14 Program in Virology, Harvard Medical School, Boston, MA  02115, USA; 15 John A. Paulson School of Engineering & Applied Sciences, Harvard  University, Cambridge, MA 02138, USA; 16 Program in Immunology, Harvard Medical  School, Boston, MA 02115, USA; 17 Division of Pediatric Hematology/Oncology, Boston  Children’s Hospital, Boston, MA 02115, USA; 18 Division of Gastroenterology, Hepatology,  and Nutrition, Boston Children’s Hospital, Boston, MA 02115, USA; 19 Aix-Marseille  University, INSERM, INRA, C2VN, Marseille, France; 20 Université Côte d’Azur, CNRS,  IPMC, Sophia-Antipolis, France; 21 Comprehensive Pneumology Center & Institute of  Lung Biology and Disease, Helmholtz Zentrum München, Munich, Germany; 22 German  Center for Lung Research, Munich, Germany; 23 Institute of Computational Biology,  Helmholtz Zentrum München, Munich, Germany; 24 Research Unit Lung Repair and  Regeneration, Helmholtz Zentrum München, Munich, Germany; 25 Division of  Neonatology, Department of Pediatrics, Vanderbilt University Medical Center, Nashville,  TN 37232, USA; 26 Divison of Allergy, Pulmonary, and Critical Care Medicine, Department  of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA; 27 Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA  02114, USA; 28 Division of Gastroenterology, Brigham and Women’s Hospital, Boston, MA  02115, USA; 29 Division of Allergy and Clinical Immunology, Department of Medicine,  Brigham and Women’s Hospital, Boston, MA 02115, USA; 30 University of California,  Berkeley, CA 94720, USA; 31 University of Washington, Seattle, WA 98195, USA; 32 Dana  Farber Cancer Institute, Boston, MA 02115, USA; 33 Harvard Medical School, Boston, MA  02115, USA; 34 Stem Cell & Gene Therapy Program, Fred Hutchinson Cancer Research  Center, Seattle, WA 98109, USA; 35 Department of Medicine, University of Washington,  Seattle, WA 98195, USA; 36 Seattle Children’s Hospital, Seattle, WA 98145, USA; 37 Department of Microbiology & Molecular Genetics, University of Pittsburgh School of  Medicine, Pittsburgh, PA 15219, USA; 38 Center for Vaccine Research, University of  Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA; 39 Division of Pulmonary,  Allergy, and Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA; 40 UPMC Children’s Hospital of Pittsburgh, Pittsburgh, PA  15224, USA; 41 Department of Pediatrics, University of Pittsburgh School of Medicine,  Pittsburgh, PA 15224, USA; 42 Department of Infection, Immunity & Cardiovascular  Disease, The Medical School and The Florey; Institute for Host Pathogen Interactions, University of Sheffield, Sheffield, S10 2TN, UK; 43 Department of Medicine, Vanderbilt  University Medical Center, Nashville, TN 37232, USA; 44 Department of Cell and  Developmental Biology, Vanderbilt University Medical Center, Nashville, TN 37240, USA; 45 Department of Veterans Affairs Medical Center, Nashville, TN 37212, USA; 46 Department of Infection & Immunity, University College London, London, UK; 47 Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA; 48 Department of  Mathematics, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; 49 Harvard Stem Cell Institute, Cambridge, MA 02138, USA



There is pressing urgency to understand the pathogenesis of the severe acute respiratory  syndrome coronavirus clade 2 (SARS-CoV-2) which causes the disease  COVID-19. SARS-CoV2 spike (S)-protein binds ACE2, and in concert with host proteases,  principally TMPRSS2, promotes cellular entry. The cell subsets targeted by SARS-CoV-2 in  host tissues, and the factors that regulate ACE2 expression, remain unknown. Here, we  leverage human, non-human primate, and mouse single-cell RNA-sequencing (scRNA- seq) datasets across health and disease to uncover putative targets of SARS-CoV-2  amongst tissue-resident cell subsets. We identify ACE2 and TMPRSS2 co-expressing cells  within lung type II pneumocytes, ileal absorptive enterocytes, and nasal goblet secretory  cells. Strikingly, we discover that ACE2 is a human interferonstimulated gene (ISG) in  vitro using airway epithelial cells, and extend our findings to in vivo viral infections. Our  data suggest that SARS-CoV-2 could exploit species-specific interferon-driven upregulation of ACE2, a tissue-protective mediator during lung injury, to enhance  infection.

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


A #multibasic #cleavage site in the #spike protein of #SARS-CoV-2 is essential for #infection of  #human #lung cells (Cell Press, abstract)

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

Journal pre-proof | DOI: 10.1016/j.molcel.2020.04.022

This is a PDF file of an accepted peer-reviewed article but is not yet the definitive version  of record. This version will undergo additional copyediting, typesetting and  review before it is published in its final form, but we are providing this version to give  early visibility of the article. Please note that, during the production process, errors may  be discovered which could affect the content, and all legal disclaimers that apply to the  journal pertain.

© 2020 The Author(s).

A multibasic cleavage site in the spike protein of SARS-CoV-2 is essential for infection of  human lung cells

Markus Hoffmann1,*, Hannah Kleine-Weber1,2, Stefan Pöhlmann1,2,3* 6 Deutsches  Primatenzentrum – Leibniz Institut für Primatenforschung, Göttingen, Germany; 7  Faculty of Biology and Psychology, University Göttingen, Göttingen, Germany; 8 Lead  contact

* Correspondence: mhoffmann@dpz.eu (Markus Hoffmann) and spoehlmann@dpz.eu  (Stefan  Pöhlmann)



The pandemic coronavirus SARS-CoV-2 threatens public health worldwide. The viral  spike protein mediates SARS-CoV-2 entry into host cells and harbors a S1/S2 cleavage site  containing multiple arginine residues (multibasic) not found in closely related animal  coronaviruses. However, the role of this multibasic cleavage site in SARS-CoV-2 infection  is unknown. Here, we report that the cellular protease furin cleaves the spike protein at  the S1/S2 site and that cleavage is essential for S protein-mediated cell-cell fusion and  entry into human lung cells. Moreover, optimizing the S1/S2 site increased cell-cell but  not virus-cell fusion, suggesting that the corresponding viral variants might exhibit  increased cell-cell spread and potentially altered virulence. Our results suggest that  acquisition of a S1/S2 multibasic cleavage site was essential for SARS-CoV-2 infection of  humans and identify furin as a potential target for therapeutic intervention.

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


#Endothelial cell #infection and #endotheliitis in #COVID19 (Lancet, summary)

[Source: The Lancet, full page: (LINK). Summary, edited.]

Endothelial cell infection and endotheliitis in COVID-19

Published Online April 17, 2020 | DOI: https://doi.org/10.1016/S0140-6736(20)30937-5

Zsuzsanna Varga, Andreas J Flammer, Peter Steiger, Martina Haberecker, Rea  Andermatt, Annelies S Zinkernagel, Mandeep R Mehra, Reto A Schuepbach, *Frank  Ruschitzka, Holger Moch – frank.ruschitzka@usz.ch


Department of Pathology and Molecular Pathology (ZV, MH, HM), Department of  Cardiology, University Heart Center (AJF, FR), Institute for Intensive Care Medicine (PS,  RA, RAS), and Division of Infectious Diseases (ASZ), University Hospital Zurich, CH-8091  Zurich, Switzerland; and Department of Internal Medicine, Brigham and Women’s  Hospital and Harvard Medical School, Boston, MA, USA (MRM)


Cardiovascular complications are rapidly emerging as a key threat in coronavirus  disease 2019 (COVID-19) in addition to respiratory disease. The mechanisms underlying  the disproportionate effect of severe acute respiratory syndrome coronavirus 2 (SARS- CoV-2) infection on patients with cardiovascular comorbidities, however, remain  incompletely understood.1,2 SARS-CoV-2 infects the host using the angiotensin  converting enzyme 2 (ACE2) receptor, which is expressed in several organs, including the  lung, heart, kidney, and intestine. ACE2 receptors are also expressed by endothelial  cells.3 Whether vascular derangements in COVID-19 are due to endothelial cell involvement by the virus is currently unknown. Intriguingly, SARS-CoV-2 can directly  infect engineered human blood vessel organoids in vitro.4 Here we demonstrate  endothelial cell involvement across vascular beds of different organs in a series of  patients with COVID-19 (further case details are provided in the appendix).


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


#MERS #coronavirus #nucleocapsid protein suppresses type I and type III #interferon induction by targeting RIG-I signaling (J Virol., abstract)

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

Middle East respiratory syndrome coronavirus nucleocapsid protein suppresses type I and type III interferon induction by targeting RIG-I signaling

Chi-You Chang, Helene Minyi Liu, Ming-Fu Chang, Shin C. Chang

DOI: 10.1128/JVI.00099-20



Type I and type III interferons (IFNs) are the frontlines of antiviral defense mechanism that trigger hundreds of downstream antiviral genes. In this study, we observed that MERS-CoV nucleocapsid (N) protein suppresses type I and III IFN gene expression. The N protein suppresses Sendai virus-induced IFN-β and IFN-λ1 by reducing their promoter activity and mRNA levels as well as downstream IFN stimulated genes (ISGs). Retinoic acid-inducible gene-I (RIG-I) is known to recognize viral RNA and induce IFN expression through tripartite motif-containing protein 25 (TRIM25)-mediated ubiquitination of RIG-I caspase activation and recruitment domains (CARDs). We discovered that MERS-CoV N protein suppresses RIG-I-CARD-, but not MDA5-CARD-induced IFN-β and IFN-λ1 promoter activity. By interacting with TRIM25, N protein impedes RIG-I ubiquitination and activation and inhibits the phosphorylation of transcription factors IFN-regulatory factor 3 (IRF3) and NF-κB that are known to be important for IFN gene activation. By employing recombinant Sindbis virus-EGFP replication system, we showed that viral N protein downregulated the production of not only IFN mRNA but also bioactive IFN proteins. Taken together, MERS-CoV N protein functions as an IFN antagonist. It suppresses RIG-I-induced type I and type III IFN production by interfering with TRIM25-mediated RIG-I ubiquitination. Our study sheds light on the pathogenic mechanism of how MERS-CoV causes disease.



MERS-CoV causes death of about 35% of patients. Published studies showed that some coronaviruses are capable of suppressing interferon (IFN) expression in the early phase of infection and MERS-CoV proteins can modulate host immune response. In this study, we demonstrated that MERS-CoV nucleocapsid (N) protein suppresses the production of both type I and type III IFNs via sequestering TRIM25, an E3 ubiquitin ligase that is essential for activating RIG-I signaling pathway. Ectopic expression of TRIM25 rescues the suppressive effect of the N protein. In addition, the C-terminal domain of the viral N protein plays a pivotal role in the suppression of IFN-β promoter activity. Our findings reveal how MERS-CoV evades innate immunity and provide insights into the interplay between host immune response and viral pathogenicity.

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

Keywords: MERS-CoV; Interferons; Viral pathogenesis.