#Structure of the #SARS-CoV-2 #spike receptor-binding domain bound to the #ACE2 receptor (Nature, abstract)

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

Structure of the SARS-CoV-2 spike receptor-binding domain bound to the ACE2 receptor

Jun Lan, Jiwan Ge, Jinfang Yu, Sisi Shan, Huan Zhou, Shilong Fan, Qi Zhang, Xuanling Shi, Qisheng Wang, Linqi Zhang & Xinquan Wang

Nature (2020)

 

Abstract

A novel and highly pathogenic coronavirus (SARS-CoV-2) has caused an outbreak in Wuhan city, Hubei province of China since December 2019, and soon spread nationwide and spilled over to other countries around the world1–3. To better understand the initial step of infection at an atomic level, we determined the crystal structure of the SARS-CoV-2 spike receptor-binding domain (RBD) bound to the cell receptor ACE2 at 2.45 Å resolution. The overall ACE2-binding mode of the SARS-CoV-2 RBD is nearly identical to that of the SARS-CoV RBD, which also utilizes ACE2 as the cell receptor4. Structural analysis identified residues in the SARS-CoV-2 RBD that are critical for ACE2 binding, the majority of which either are highly conserved or share similar side chain properties with those in the SARS-CoV RBD. Such similarity in structure and sequence strongly argue for convergent evolution between the SARS-CoV-2 and SARS-CoV RBDs for improved binding to ACE2, although SARS-CoV-2 does not cluster within SARS and SARS-related coronaviruses1–3,5. The epitopes of two SARS-CoV antibodies targeting the RBD are also analysed with the SARS-CoV-2 RBD, providing insights into the future identification of cross-reactive antibodies.

Author notes: These authors contributed equally: Jun Lan, Jiwan Ge, Jinfang Yu, Sisi Shan

Affiliations: The Ministry of Education Key Laboratory of Protein Science, Beijing Advanced Innovation Center for Structural Biology, Beijing Frontier Research Center for Biological Structure, Collaborative Innovation Center for Biotherapy, School of Life Sciences, Tsinghua University, 100084, Beijing, China (Jun Lan, Jiwan Ge, Jinfang Yu, Shilong Fan & Xinquan Wang); Center for Global Health and Infectious Diseases, Comprehensive AIDS Research Center, and Beijing Advanced Innovation Center for Structural Biology, School of Medicine, Tsinghua University, Beijing, 100084, China (Sisi Shan, Qi Zhang, Xuanling Shi & Linqi Zhang); Shanghai Synchrotron Radiation Facility, Shanghai Advanced Research Institute, Chinese Academy of Sciences, Shanghai, 201204, China (Huan Zhou & Qisheng Wang

Corresponding authors to Linqi Zhang or Xinquan Wang.

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

—–

#Organ‐protective Effect of #ACE2 and its Effect on the #Prognosis of #COVID19 (J Med Virol., abstract)

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

Organ‐protective Effect of Angiotensin‐converting Enzyme 2 and its Effect on the Prognosis of COVID‐19

Hao Cheng,  Yan Wang,  Gui‐Qiang Wang

First published: 27 March 2020 | DOI: https://doi.org/10.1002/jmv.25785

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.25785

 

Abstract

This article reviews the correlation between ACE2 and severe risk factors for COVID‐19 and the possible mechanisms. Angiotensin‐converting enzyme 2 (ACE2) is a crucial component of the renin‐angiotensin system (RAS). The classical RAS ACE‐Ang II‐AT1R regulatory axis and the ACE2‐Ang1‐7‐MasR counter‐regulatory axis play an essential role in maintaining homeostasis in humans. ACE2 is widely distributed in the heart, kidneys, lungs, and testes. ACE2 antagonizes the activation of the classical RAS system and protects against organ damage, protecting against hypertension, diabetes, and cardiovascular disease. Similar to SARS‐CoV, SARS‐CoV‐2 also uses the ACE2 receptor to invade human alveolar epithelial cells. ARDS is a clinical high‐mortality disease, and ACE2 has a protective effect on this type of acute lung injury. Current research shows that the poor prognosis of patients with COVID‐19 is related to factors such as sex (male), age (higher than 60 years), underlying diseases (hypertension, diabetes, and cardiovascular disease), secondary ARDS, and other relevant factors. Because of these protective effects of ACE2 on chronic underlying diseases and ARDS, the development of spike protein‐based vaccine and drugs enhancing ACE2 activity may become one of the most promising approaches for the treatment of COVID‐19 in the future.

This article is protected by copyright. All rights reserved.

Keywords: SARS-CoV-2; COVID-19; ACE2.

—–

#Structural #basis for the #recognition of #SARS-CoV-2 by full-length #human #ACE2 (Science, abstract)

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

Structural basis for the recognition of SARS-CoV-2 by full-length human ACE2

Renhong Yan1,2, Yuanyuan Zhang1,2,*, Yaning Li3,*, Lu Xia1,2, Yingying Guo1,2, Qiang Zhou1,2,†

1 Key Laboratory of Structural Biology of Zhejiang Province, Institute of Biology, Westlake Institute for Advanced Study, 18 Shilongshan Road, Hangzhou 310024, Zhejiang Province, China. 2 School of Life Sciences, Westlake University, 18 Shilongshan Road, Hangzhou 310024, Zhejiang Province, China. 3 Beijing Advanced Innovation Center for Structural Biology, Tsinghua-Peking Joint Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing 100084, China.

†Corresponding author. Email: zhouqiang@westlake.edu.cn

* These authors contributed equally to this work.

Science  27 Mar 2020: Vol. 367, Issue 6485, pp. 1444-1448 | DOI: 10.1126/science.abb2762

 

How SARS-CoV-2 binds to human cells

Scientists are racing to learn the secrets of severe acute respiratory syndrome–coronavirus 2 (SARS-CoV-2), which is the cause of the pandemic disease COVID-19. The first step in viral entry is the binding of the viral trimeric spike protein to the human receptor angiotensin-converting enzyme 2 (ACE2). Yan et al. present the structure of human ACE2 in complex with a membrane protein that it chaperones, B0AT1. In the context of this complex, ACE2 is a dimer. A further structure shows how the receptor binding domain of SARS-CoV-2 interacts with ACE2 and suggests that it is possible that two trimeric spike proteins bind to an ACE2 dimer. The structures provide a basis for the development of therapeutics targeting this crucial interaction.

Science, this issue p. 1444

 

Abstract

Angiotensin-converting enzyme 2 (ACE2) is the cellular receptor for severe acute respiratory syndrome–coronavirus (SARS-CoV) and the new coronavirus (SARS-CoV-2) that is causing the serious coronavirus disease 2019 (COVID-19) epidemic. Here, we present cryo–electron microscopy structures of full-length human ACE2 in the presence of the neutral amino acid transporter B0AT1 with or without the receptor binding domain (RBD) of the surface spike glycoprotein (S protein) of SARS-CoV-2, both at an overall resolution of 2.9 angstroms, with a local resolution of 3.5 angstroms at the ACE2-RBD interface. The ACE2-B0AT1 complex is assembled as a dimer of heterodimers, with the collectrin-like domain of ACE2 mediating homodimerization. The RBD is recognized by the extracellular peptidase domain of ACE2 mainly through polar residues. These findings provide important insights into the molecular basis for coronavirus recognition and infection.

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

—–

#Tropism of the Novel #Coronavirus #SARS-CoV-2 in #Human #Respiratory Tract: An Analysis in Ex Vivo and In Vitro Cultures (SSRN, abstract)

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

Tropism of the Novel Coronavirus SARS-CoV-2 in Human Respiratory Tract: An Analysis in Ex Vivo and In Vitro Cultures

25 Pages Posted: 25 Mar 2020

Kenrie PY Hui, The University of Hong Kong – School of Public Health; Man-Chun Cheung, The University of Hong Kong – School of Public Health; Ranawaka APM Perera, The University of Hong Kong – School of Public Health; Ka-Chun Ng, The University of Hong Kong – School of Public Health; Christine BT Bui, The University of Hong Kong – School of Public Health; John CW Ho, The University of Hong Kong – School of Public Health; Mandy MT Ng, The University of Hong Kong – School of Public Health; Denise IT Kuok, The University of Hong Kong – School of Public Health; Kendrick C. Shih, The University of Hong Kong – Department of Ophthalmology; SW Tsao, The University of Hong Kong – School of Biomedical Sciences; Leo LM Poon, The University of Hong Kong – School of Public Health; Malik Peiris, The University of Hong Kong – School of Public Health; John M. Nicholls, The University of Hong Kong – Department of Pathology; Michael CW Chan, The University of Hong Kong – School of Public Health

 

Abstract

Background:

A novel human coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in December 2019, to cause a respiratory disease (COVID-19) of varying severity in Wuhan China, subsequently spreading to other parts of China and beyond.

Methods:

We infected ex vivo explant cultures of the human conjunctiva, bronchus and lung, and in vitro cultures of primary human alveolar epithelial cells and macrophages with SARS-CoV-2, and assessed viral tropism, replication competence and innate immune responses, in comparison with SARS-CoV, MERS-CoV, and the 2009 pandemic influenza H1N1 (pdmH1N1) virus.

Findings:

SARS-CoV-2 infected ciliated, mucus secreting and club cells of bronchial epithelium, spindled morphologically type I pneumocytes in the lung, and the conjunctival mucosa. Virus replication competence of SARS-CoV-2 in the bronchus was higher than that of SARS-CoV but lower than pdmH1N1. SARS-CoV-2 replication was comparable with SARS-CoV and pdmH1N1 in the lung but was lower than MERS-CoV. SARS-CoV-2 virus was a less potent inducer of pro-inflammatory cytokines compared with H5N1 and MERS-CoV. Influenza virus infection of alveolar epithelial cells increased ACE2 expression.

Interpretation:

The conjunctival epithelium and the conducting airways appear to be potential portals of infection of SARS-CoV-2. Both SARS-CoV and SARS-CoV-2 replicated comparably in the alveolar epithelium explaining the progression of infection to a primary viral pneumonia.

___

Funding Statement: US National Institute of Allergy and Infectious Diseases (NIAID) under Centers of Excellence for Influenza Research and Surveillance (CEIRS) contract no. HHSN272201400006C and the Theme Based Research Scheme (Ref: T11-705/14N), Hong Kong Special Administrative Region.

Declaration of Interests: There is no conflict of interest for all authors.

Ethics Approval Statement: All experiments were carried out in a Bio-safety level 3 (BSL-3) facility. Informed consent was obtained from all subjects and approval was granted by the Institutional Review Board (IRB) of the University of Hong Kong and the Hospital Authority (Hong Kong West) (approval no: UW 20-167).

Keywords: SARS-CoV-2; COVID-19; tropism; ex vivo; explants; respiratory tract; conjunctiva; pathogenesis; risk assessment; transmissibility

Suggested Citation: Hui, Kenrie PY and Cheung, Man-Chun and Perera, Ranawaka APM and Ng, Ka-Chun and Bui, Christine BT and Ho, John CW and Ng, Mandy MT and Kuok, Denise IT and Shih, Kendrick C. and Tsao, SW and Poon, Leo LM and Peiris, Malik and Nicholls, John M. and Chan, Michael CW, Tropism of the Novel Coronavirus SARS-CoV-2 in Human Respiratory Tract: An Analysis in Ex Vivo and In Vitro Cultures (3/10/2020). Available at SSRN: https://ssrn.com/abstract=3552870 or http://dx.doi.org/10.2139/ssrn.3552870

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

—–

Predicting the Angiotensin Converting Enzyme 2 (#ACE2) Utilizing Capability as the #Receptor of #SARS-CoV-2 (Microbes Infect., abstract)

[Source: US National Library of Medicine, full page: (LINK). Abstract, edited.]

Microbes Infect 2020 Mar 18 [Online ahead of print]

Predicting the Angiotensin Converting Enzyme 2 (ACE2) Utilizing Capability as the Receptor of SARS-CoV-2

Ye Qiu 1, Yuan-Bo Zhao 1, Qiong Wang 1, Jin-Yan Li 1, Zhi-Jian Zhou 1, Ce-Heng Liao 1, Xing-Yi Ge 2

Affiliations: 1 Hunan Provincial Key Laboratory of Medical Virology, Institute of Pathogen Biology and Immunology, College of Biology, Hunan University, 27 Tianma Rd., Changsha, Hunan, 410012, China. 2 Hunan Provincial Key Laboratory of Medical Virology, Institute of Pathogen Biology and Immunology, College of Biology, Hunan University, 27 Tianma Rd., Changsha, Hunan, 410012, China. Electronic address: xyge@hnu.edu.cn.

PMID: 32199943 DOI: 10.1016/j.micinf.2020.03.003

 

Abstract

SARS-CoV-2, the newly identified human coronavirus causing severe pneumonia epidemic, was probably originated from Chinese horseshoe bats. However, direct transmission of the virus from bats to humans is unlikely due to lack of direct contact, implying the existence of unknown intermediate hosts. Angiotensin converting enzyme 2 (ACE2) is the receptor of SARS-CoV-2, but only ACE2s of certain species can be utilized by SARS-CoV-2. Here, we evaluated and ranked the receptor-utilizing capability of ACE2s from various species by phylogenetic clustering and sequence alignment with the currently known ACE2s utilized by SARS-CoV-2. As a result, we predicted that SARS-CoV-2 tends to utilize ACE2s of various mammals, except murines, and some birds, such as pigeon. This prediction may help to screen the intermediate hosts of SARS-CoV-2.

Keywords: SARS-CoV-2; angiotensin converting enzyme 2 (ACE2); coronavirus; phylogenetic analysis; receptor utilization.

Copyright © 2020 Institut Pasteur. Published by Elsevier Masson SAS. All rights reserved.

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

—–

#Coronavirus #endoribonuclease targets viral polyuridine sequences to evade activating #host sensors (Proc Natl Acad Sci USA, abstract)

[Source: Proceedings of the National Academy of Sciences of the United States of America, full page: (LINK). Abstract, edited.]

Coronavirus endoribonuclease targets viral polyuridine sequences to evade activating host sensors

Matthew Hackbart, Xufang Deng, and Susan C. Baker

PNAS first published March 20, 2020 | DOI: https://doi.org/10.1073/pnas.1921485117

Edited by Stanley Perlman, University of Iowa, Iowa City, IA, and accepted by Editorial Board Member Linda J. Saif March 5, 2020 (received for review December 9, 2019)

 

Significance

Cells carry sensors that are primed to detect invading viruses. To avoid being recognized, coronaviruses express factors that interfere with host immune sensing pathways. Previous studies revealed that a coronavirus endoribonuclease (EndoU) delays activation of the host sensor system, but the mechanism was not known. Here, we report that EndoU cleaves a viral polyuridine sequence that would otherwise activate host immune sensors. This information may be used in developing inhibitors that target EndoU activity and prevent diseases caused by coronaviruses.

Abstract

Coronaviruses (CoVs) are positive-sense RNA viruses that can emerge from endemic reservoirs and infect zoonotically, causing significant morbidity and mortality. CoVs encode an endoribonuclease designated EndoU that facilitates evasion of host pattern recognition receptor MDA5, but the target of EndoU activity was not known. Here, we report that EndoU cleaves the 5′-polyuridines from negative-sense viral RNA, termed PUN RNA, which is the product of polyA-templated RNA synthesis. Using a virus containing an EndoU catalytic-inactive mutation, we detected a higher abundance of PUN RNA in the cytoplasm compared to wild-type−infected cells. Furthermore, we found that transfecting PUN RNA into cells stimulates a robust, MDA5-dependent interferon response, and that removal of the polyuridine extension on the RNA dampens the response. Overall, the results of this study reveal the PUN RNA to be a CoV MDA5-dependent pathogen-associated molecular pattern (PAMP). We also establish a mechanism for EndoU activity to cleave and limit the accumulation of this PAMP. Since EndoU activity is highly conserved in all CoVs, inhibiting this activity may serve as an approach for therapeutic interventions against existing and emerging CoV infections.

coronavirus – endoribonuclease – EndoU – nsp15 – interferon

 

Footnotes

1 To whom correspondence may be addressed. Email: sbaker1@luc.edu.

Author contributions: M.H., X.D., and S.C.B. designed research; M.H. performed research; M.H., X.D., and S.C.B. contributed new reagents/analytic tools; M.H. analyzed data; M.H. and S.C.B. wrote the paper; and X.D. edited the paper.

The authors declare no competing interest.

This article is a PNAS Direct Submission. S.P. is a guest editor invited by the Editorial Board.

Data deposition: The RNA sequencing data reported in this paper have been deposited in the National Center for Biotechnology Information Gene Expression Omnibus (GEO) database, https://www.ncbi.nlm.nih.gov/geo (accession no. GSE144886).

This article contains supporting information online at https://www.pnas.org/lookup/suppl/doi:10.1073/pnas.1921485117/-/DCSupplemental.

Keywords: Coronavirus; Viral pathogenesis.

—–

A Unique #Protease #Cleavage Site Predicted in the #Spike Protein of the Novel Pneumonia #Coronavirus (2019-nCoV) Potentially Related to Viral Transmissibility (Virol Sin., summary)

[Source: Virologica Sinica, full page: (LINK). Summary, edited.]

A Unique Protease Cleavage Site Predicted in the Spike Protein of the Novel Pneumonia Coronavirus (2019-nCoV) Potentially Related to Viral Transmissibility

Qiong Wang, Ye Qiu, Jin-Yan Li, Zhi-Jian Zhou, Ce-Heng Liao & Xing-Yi Ge

Virologica Sinica (2020)

___

Dear Editor, In December 2019, a novel human coronavirus caused an epidemic of severe pneumonia (Coronavirus Disease 2019, COVID-19) in Wuhan, Hubei, China (Wu et al.2020; Zhu et al.2020). So far, this virus has spread to all areas of China and even to other countries. The epidemic has caused 67,102 confirmed infections with 1526 fatal cases worldwide by February 14th, 2020. The viral infection incubation period varies from 2 to 14 days and typical clinical symptoms are fever, dry cough, dyspnea, headache, and pneumonia. Disease onset may result in progressive respiratory failure due to alveolar damage and even death (Chan et al.2020; Chen et al.2020; Huang et al.2020).

(…)

Keywords: SARS-CoV-2; COVID-19.

—–