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Structural Genomics of SARS-CoV-2 Indicates Evolutionary Conserved Functional Regions of Viral Proteins

Abstract (Expand)

During its first two and a half months, the recently emerged 2019 novel coronavirus, SARS-CoV-2, has already infected over one-hundred thousand people worldwide and has taken more than four thousand … lives. However, the swiftly spreading virus also caused an unprecedentedly rapid response from the research community facing the unknown health challenge of potentially enormous proportions. Unfortunately, the experimental research to understand the molecular mechanisms behind the viral infection and to design a vaccine or antivirals is costly and takes months to develop. To expedite the advancement of our knowledge, we leveraged data about the related coronaviruses that is readily available in public databases and integrated these data into a single computational pipeline. As a result, we provide comprehensive structural genomics and interactomics roadmaps of SARS-CoV-2 and use this information to infer the possible functional differences and similarities with the related SARS coronavirus. All data are made publicly available to the research community.

Authors: Suhas Srinivasan, Hongzhu Cui, Ziyang Gao, Ming Liu, Senbao Lu, Winnie Mkandawire, Oleksandr Narykov, Mo Sun, Dmitry Korkin

Date Published: 1st Apr 2020

Publication Type: Journal

COVID-19: Attacks the 1-Beta Chain of Hemoglobin and Captures the Porphyrin to Inhibit Human Heme Metabolism

Abstract (Expand)

The novel coronavirus pneumonia (COVID-19) is an infectious acute respiratory infection caused by the novel coronavirus. The virus is a positive-strand RNA virus with high homology to bat coronavirus. … In this study, conserved domain analysis, homology modeling, and molecular docking were used to compare the biological roles of certain proteins of the novel coronavirus. The results showed the ORF8 and surface glycoprotein could bind to the porphyrin, respectively. At the same time, orf1ab, ORF10, and ORF3a proteins could coordinate attack the heme on the 1-beta chain of hemoglobin to dissociate the iron to form the porphyrin. The attack will cause less and less hemoglobin that can carry oxygen and carbon dioxide. The lung cells have extremely intense poisoning and inflammatory due to the inability to exchange carbon dioxide and oxygen frequently, which eventually results in ground-glass-like lung images. The mechanism also interfered with the normal heme anabolic pathway of the human body, is expected to result in human disease. According to the validation analysis of these finds, chloroquine could prevent orf1ab, ORF3a, and ORF10 to attack the heme to form the porphyrin, and inhibit the binding of ORF8 and surface glycoproteins to porphyrins to a certain extent, effectively relieve the symptoms of respiratory distress. Favipiravir could inhibit the envelope protein and ORF7a protein bind to porphyrin, prevent the virus from entering host cells, and catching free porphyrins. Because the novel coronavirus is dependent on porphyrins, it may originate from an ancient virus. Therefore, this research is of high value to contemporary biological experiments, disease prevention, and clinical treatment.

Authors: Liu Wenzhong, Li Hualan

Date Published: 30th Mar 2020

Publication Type: Journal

Renin–Angiotensin–Aldosterone System Inhibitors in Patients with Covid-19

Abstract

Not specified

Authors: Muthiah Vaduganathan, Orly Vardeny, Thomas Michel, John J.V. McMurray, Marc A. Pfeffer, Scott D. Solomon

Date Published: 30th Mar 2020

Publication Type: Journal

Clinical and immunologic features in severe and moderate Coronavirus Disease 2019

Abstract

Not specified

Authors: Guang Chen, Di Wu, Wei Guo, Yong Cao, Da Huang, Hongwu Wang, Tao Wang, Xiaoyun Zhang, Huilong Chen, Haijing Yu, Xiaoping Zhang, Minxia Zhang, Shiji Wu, Jianxin Song, Tao Chen, Meifang Han, Shusheng Li, Xiaoping Luo, Jianping Zhao, Qin Ning

Date Published: 27th Mar 2020

Publication Type: Journal

Potent human neutralizing antibodies elicited by SARS-CoV-2 infection

Abstract (Expand)

The pandemic caused by emerging coronavirus SARS-CoV-2 presents a serious global public health emergency in urgent need of prophylactic and therapeutic interventions. SARS CoV-2 cellular entry depends … on binding between the viral Spike protein receptor-binding domain (RBD) and the angiotensin converting enzyme 2 (ACE2) target cell receptor. Here, we report on the isolation and characterization of 206 RBD-specific monoclonal antibodies (mAbs) derived from single B cells of eight SARS-CoV-2 infected individuals. These mAbs come from diverse families of antibody heavy and light chains without apparent enrichment for particular families in the repertoire. In samples from one patient selected for further analyses, we found coexistence of germline and germline divergent clones. Both clone types demonstrated impressive binding and neutralizing activity against pseudovirus and live SARS-CoV-2. However, the antibody neutralizing potency is determined by competition with ACE2 receptor for RBD binding. Surprisingly, none of the SARS CoV 2 antibodies nor the infected plasma cross-reacted with RBDs from either SARS CoV or MERS CoV although substantial plasma cross reactivity to the trimeric Spike proteins from SARS-CoV and MERS-CoV was found. These results suggest that antibody response to RBDs is viral species-specific while that cross-recognition target regions outside the RBD. The specificity and neutralizing characteristics of this plasma cross-reactivity requires further investigation. Nevertheless, the diverse and potent neutralizing antibodies identified here are promising candidates for prophylactic and therapeutic SARS-CoV-2 interventions.

Authors: Bin Ju, Qi Zhang, Xiangyang Ge, Ruoke Wang, Jiazhen Yu, Sisi Shan, Bing Zhou, Shuo Song, Xian Tang, Jinfang Yu, Jiwan Ge, Jun Lan, Jing Yuan, Haiyan Wang, Juanjuan Zhao, Shuye Zhang, Youchun Wang, Xuanling Shi, Lei Liu, Xinquan Wang, Zheng Zhang, Linqi Zhang

Date Published: 25th Mar 2020

Publication Type: Tech report

Safety, Tolerability, Pharmacokinetics, and Antimalarial Activity of the Novel Plasmodium Phosphatidylinositol 4-Kinase Inhibitor MMV390048 in Healthy Volunteers

Abstract (Expand)

MMV390048 is a novel antimalarial compound that inhibits Plasmodium phosphatidylinositol-4-kinase. The safety, tolerability, pharmacokinetic profile, and antimalarial activity of MMV390048 were determined …le, and antimalarial activity of MMV390048 were determined in healthy volunteers in three separate studies. A first-in-human, double-blind, randomized, placebo-controlled, single-ascending-dose study was performed. Additionally, a volunteer infection study investigated the antimalarial activity of MMV390048 using the Plasmodium falciparum induced blood-stage malaria (IBSM) model.

Authors: Phumla Sinxadi, Cristina Donini, Hilary Johnstone, Grant Langdon, Lubbe Wiesner, Elizabeth Allen, Stephan Duparc, Stephan Chalon, James S. McCarthy, Ulrike Lorch, Kelly Chibale, Jörg Möhrle, Karen I. Barnes

Date Published: 24th Mar 2020

Publication Type: Journal

A SARS-CoV-2-Human Protein-Protein Interaction Map Reveals Drug Targets and Potential Drug-Repurposing

Abstract (Expand)

An outbreak of the novel coronavirus SARS-CoV-2, the causative agent of COVID-19 respiratory disease, has infected over 290,000 people since the end of 2019, killed over 12,000, and caused worldwide … social and economic disruption1,2. There are currently no antiviral drugs with proven efficacy nor are there vaccines for its prevention. Unfortunately, the scientific community has little knowledge of the molecular details of SARS-CoV-2 infection. To illuminate this, we cloned, tagged and expressed 26 of the 29 viral proteins in human cells and identified the human proteins physically associated with each using affinity-purification mass spectrometry (AP-MS), which identified 332 high confidence SARS-CoV-2-human protein-protein interactions (PPIs). Among these, we identify 67 druggable human proteins or host factors targeted by 69 existing FDA-approved drugs, drugs in clinical trials and/or preclinical compounds, that we are currently evaluating for efficacy in live SARS-CoV-2 infection assays. The identification of host dependency factors mediating virus infection may provide key insights into effective molecular targets for developing broadly acting antiviral therapeutics against SARS-CoV-2 and other deadly coronavirus strains.

Authors: David E. Gordon, Gwendolyn M. Jang, Mehdi Bouhaddou, Jiewei Xu, Kirsten Obernier, Matthew J. O’Meara, Jeffrey Z. Guo, Danielle L. Swaney, Tia A. Tummino, Ruth Hüttenhain, Robyn M. Kaake, Alicia L. Richards, Beril Tutuncuoglu, Helene Foussard, Jyoti Batra, Kelsey Haas, Maya Modak, Minkyu Kim, Paige Haas, Benjamin J. Polacco, Hannes Braberg, Jacqueline M. Fabius, Manon Eckhardt, Margaret Soucheray, Melanie J. Bennett, Merve Cakir, Michael J McGregor, Qiongyu Li, Zun Zar Chi Naing, Yuan Zhou, Shiming Peng, Ilsa T. Kirby, James E. Melnyk, John S. Chorba, Kevin Lou, Shizhong A. Dai, Wenqi Shen, Ying Shi, Ziyang Zhang, Inigo Barrio-Hernandez, Danish Memon, Claudia Hernandez-Armenta, Christopher J.P. Mathy, Tina Perica, Kala B. Pilla, Sai J. Ganesan, Daniel J. Saltzberg, Rakesh Ramachandran, Xi Liu, Sara B. Rosenthal, Lorenzo Calviello, Srivats Venkataramanan, Yizhu Lin, Stephanie A. Wankowicz, Markus Bohn, Raphael Trenker, Janet M. Young, Devin Cavero, Joe Hiatt, Theo Roth, Ujjwal Rathore, Advait Subramanian, Julia Noack, Mathieu Hubert, Ferdinand Roesch, Thomas Vallet, Björn Meyer, Kris M. White, Lisa Miorin, David Agard, Michael Emerman, Davide Ruggero, Adolfo García-Sastre, Natalia Jura, Mark von Zastrow, Jack Taunton, Olivier Schwartz, Marco Vignuzzi, Christophe d’Enfert, Shaeri Mukherjee, Matt Jacobson, Harmit S. Malik, Danica G. Fujimori, Trey Ideker, Charles S. Craik, Stephen Floor, James S. Fraser, John Gross, Andrej Sali, Tanja Kortemme, Pedro Beltrao, Kevan Shokat, Brian K. Shoichet, Nevan J. Krogan

Date Published: 22nd Mar 2020

Publication Type: Unpublished

Network Bioinformatics Analysis Provides Insight into Drug Repurposing for COVID-2019

Abstract (Expand)

The COVID-2019 disease caused by the SARS-CoV-2 virus (aka 2019-nCoV) has raised significant health concerns in China and worldwide. While novel drug discovery and vaccine studies are long, repurposing … old drugs against the COVID-2019 epidemic can help identify treatments, with known preclinical, pharmacokinetic, pharmacodynamic, and toxicity profiles, which can rapidly enter Phase 3 or 4 or can be used directly in clinical settings. In this study, we presented a novel network based drug repurposing platform to identify potential drugs for the treatment of COVID-2019. We first analysed the genome sequence of SARS-CoV-2 and identified SARS as the closest disease, based on genome similarity between both causal viruses, followed by MERS and other human coronavirus diseases. Using our AutoSeed pipeline (text mining and database searches), we obtained 34 COVID-2019-related genes. Taking those genes as seeds, we automatically built a molecular network for which our module detection and drug prioritization algorithms identified 24 disease-related human pathways, five modules and finally suggested 78 drugs to repurpose. Following manual filtering based on clinical knowledge, we re-prioritized 30 potential repurposable drugs against COVID-2019 (including pseudoephedrine, andrographolide, chloroquine, abacavir, and thalidomide) . We hope that this data can provide critical insights into SARS-CoV-2 biology and help design rapid clinical trials of treatments against COVID-2019.

Authors: Xu Li, Jinchao Yu, Zhiming Zhang, Jing Ren, Alex E. Peluffo, Wen Zhang, Yujie Zhao, Kaijing Yan, Daniel Cohen, Wenjia Wang

Date Published: 18th Mar 2020

Publication Type: Tech report

Breadth of concomitant immune responses prior to patient recovery: a case report of non-severe COVID-19

Abstract

Not specified

Authors: Irani Thevarajan, Thi H. O. Nguyen, Marios Koutsakos, Julian Druce, Leon Caly, Carolien E. van de Sandt, Xiaoxiao Jia, Suellen Nicholson, Mike Catton, Benjamin Cowie, Steven Y. C. Tong, Sharon R. Lewin, Katherine Kedzierska

Date Published: 16th Mar 2020

Publication Type: Journal

SARS-CoV-2 receptor ACE2 and TMPRSS2 are predominantly expressed in a transient secretory cell type in subsegmental bronchial branches

Abstract (Expand)

The SARS-CoV-2 pandemic affecting the human respiratory system severely challenges public health and urgently demands for increasing our understanding of COVID-19 pathogenesis, especially host factors … facilitating virus infection and replication. SARS-CoV-2 was reported to enter cells via binding to ACE2, followed by its priming by TMPRSS2. Here, we investigate ACE2 and TMPRSS2 expression levels and their distribution across cell types in lung tissue (twelve donors, 39,778 cells) and in cells derived from subsegmental bronchial branches (four donors, 17,521 cells) by single nuclei and single cell RNA sequencing, respectively. While TMPRSS2 is expressed in both tissues, in the subsegmental bronchial branches ACE2 is predominantly expressed in a transient secretory cell type. Interestingly, these transiently differentiating cells show an enrichment for pathways related to RHO GTPase function and viral processes suggesting increased vulnerability for SARS-CoV-2 infection. Our data provide a rich resource for future investigations of COVID-19 infection and pathogenesis.

Authors: Soeren Lukassen, Robert Lorenz Chua, Timo Trefzer, Nicolas C. Kahn, Marc A. Schneider, Thomas Muley, Hauke Winter, Michael Meister, Carmen Veith, Agnes W. Boots, Bianca P. Hennig, Michael Kreuter, Christian Conrad, Roland Eils

Date Published: 14th Mar 2020

Publication Type: Tech report

SARS-CoV-2 invades host cells via a novel route: CD147-spike protein

Abstract (Expand)

Currently, COVID-19 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been widely spread around the world; nevertheless, so far there exist no specific antiviral drugs for … treatment of the disease, which poses great challenge to control and contain the virus. Here, we reported a research finding that SARS-CoV-2 invaded host cells via a novel route of CD147-spike protein (SP). SP bound to CD147, a receptor on the host cells, thereby mediating the viral invasion. Our further research confirmed this finding. First, in vitro antiviral tests indicated Meplazumab, an anti-CD147 humanized antibody, significantly inhibited the viruses from invading host cells, with an EC50 of 24.86 μg/mL and IC50 of 15.16 μg/mL. Second, we validated the interaction between CD147 and SP, with an affinity constant of 1.85×10-7M. Co-Immunoprecipitation and ELISA also confirmed the binding of the two proteins. Finally, the localization of CD147 and SP was observed in SARS-CoV-2 infected Vero E6 cells by immuno-electron microscope. Therefore, the discovery of the new route CD147-SP for SARS-CoV-2 invading host cells provides a critical target for development of specific antiviral drugs.

Authors: Ke Wang, Wei Chen, Yu-Sen Zhou, Jian-Qi Lian, Zheng Zhang, Peng Du, Li Gong, Yang Zhang, Hong-Yong Cui, Jie-Jie Geng, Bin Wang, Xiu-Xuan Sun, Chun-Fu Wang, Xu Yang, Peng Lin, Yong-Qiang Deng, Ding Wei, Xiang-Min Yang, Yu-Meng Zhu, Kui Zhang, Zhao-Hui Zheng, Jin-Lin Miao, Ting Guo, Ying Shi, Jun Zhang, Ling Fu, Qing-Yi Wang, Huijie Bian, Ping Zhu, Zhi-Nan Chen

Date Published: 14th Mar 2020

Publication Type: Tech report

Reinfection could not occur in SARS-CoV-2 infected rhesus macaques

Abstract (Expand)

Abstract An outbreak of the Corona Virus Disease 2019 (COVID-19), caused by the severe acute respiratory syndrome CoV-2 (SARS-CoV-2), began in Wuhan and spread globally. Recently, it has been reported … that discharged patients in China and elsewhere were testing positive after recovering. However, it remains unclear whether the convalescing patients have a risk of “relapse” or “reinfection”. The longitudinal tracking of re-exposure after the disappeared symptoms of the SARS-CoV-2-infected monkeys was performed in this study. We found that weight loss in some monkeys, viral replication mainly in nose, pharynx, lung and gut, as well as moderate interstitial pneumonia at 7 days post-infection (dpi) were clearly observed in rhesus monkeys after the primary infection. After the symptoms were alleviated and the specific antibody tested positively, the half of infected monkeys were rechallenged with the same dose of SARS-CoV-2 strain. Notably, neither viral loads in nasopharyngeal and anal swabs along timeline nor viral replication in all primary tissue compartments at 5 days post-reinfection (dpr) was found in re-exposed monkeys. Combined with the follow-up virologic, radiological and pathological findings, the monkeys with re-exposure showed no recurrence of COVID-19, similarly to the infected monkey without rechallenge. Taken together, our results indicated that the primary SARS-CoV-2 infection could protect from subsequent exposures, which have the reference of prognosis of the disease and vital implications for vaccine design.

Authors: Linlin Bao, Wei Deng, Hong Gao, Chong Xiao, Jiayi Liu, Jing Xue, Qi Lv, Jiangning Liu, Pin Yu, Yanfeng Xu, Feifei Qi, Yajin Qu, Fengdi Li, Zhiguang Xiang, Haisheng Yu, Shuran Gong, Mingya Liu, Guanpeng Wang, Shunyi Wang, Zhiqi Song, Wenjie Zhao, Yunlin Han, Linna Zhao, Xing Liu, Qiang Wei, Chuan Qin

Date Published: 14th Mar 2020

Publication Type: Tech report

The SARS-CoV-2 exerts a distinctive strategy for interacting with the ACE2 human receptor

Abstract (Expand)

The COVID-19 disease has plagued over 110 countries and has resulted in over 4,000 deaths within 10 weeks. We compare the interaction between the human ACE2 receptor and the SARS-CoV-2 spike protein … with that of other pathogenic coronaviruses using molecular dynamics simulations. SARS-CoV, SARS-CoV-2, and HCoV-NL63 recognize ACE2 as the natural receptor but present a distinct binding interface to ACE2 and a different network of residue-residue contacts. SARS-CoV and SARS-CoV-2 have comparable binding affinities achieved by balancing energetics and dynamics. The SARS-CoV-2–ACE2 complex contains a higher number of contacts, a larger interface area, and decreased interface residue fluctuations relative to SARS-CoV. These findings expose an exceptional evolutionary exploration exerted by coronaviruses toward host recognition. We postulate that the versatility of cell receptor binding strategies has immediate implications on therapeutic strategies.

Authors: Esther S. Brielle, Dina Schneidman-Duhovny, Michal Linial

Date Published: 12th Mar 2020

Publication Type: Tech report

Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation

Abstract (Expand)

The outbreak of a novel coronavirus (2019-nCoV) represents a pandemic threat that has been declared a public health emergency of international concern. The CoV spike (S) glycoprotein is a key target … for vaccines, therapeutic antibodies, and diagnostics. To facilitate medical countermeasure development, we determined a 3.5-angstrom-resolution cryo–electron microscopy structure of the 2019-nCoV S trimer in the prefusion conformation. The predominant state of the trimer has one of the three receptor-binding domains (RBDs) rotated up in a receptor-accessible conformation. We also provide biophysical and structural evidence that the 2019-nCoV S protein binds angiotensin-converting enzyme 2 (ACE2) with higher affinity than does severe acute respiratory syndrome (SARS)-CoV S. Additionally, we tested several published SARS-CoV RBD-specific monoclonal antibodies and found that they do not have appreciable binding to 2019-nCoV S, suggesting that antibody cross-reactivity may be limited between the two RBDs. The structure of 2019-nCoV S should enable the rapid development and evaluation of medical countermeasures to address the ongoing public health crisis.

Authors: Daniel Wrapp, Nianshuang Wang, Kizzmekia S. Corbett, Jory A. Goldsmith, Ching-Lin Hsieh, Olubukola Abiona, Barney S. Graham, Jason S. McLellan

Date Published: 12th Mar 2020

Publication Type: Journal

Therapeutic Approaches for COVID-19 Based on the Dynamics of Interferon-mediated Immune Responses

Abstract (Expand)

As the outbreak of COVID-19 has accelerated, an urgent need for finding strategies to combat the virus is growing. Thus, gaining more knowledge on the pathogenicity mechanism of SARS-CoV2, the causing … agent of COVID-19, and its interaction with the immune system is of utmost importance. Although this novel virus is not well known yet, its structural and genetic similarity with SARS-CoV as well as the comparable pattern of age-mortality relations suggest that the previous findings on SARS can be applicable for COVID-19. Therefore, a systems biology study was conducted to investigate the underlying mechanism for the differences in the age-specific mortality of SARS and the most important signaling pathways activated by the virus. The results were then validated through a literature review on COVID-19 and the other closely related viruses, SARS and MERS.

Editor:

Date Published: 12th Mar 2020

Publication Type: Tech report

Analysis of Thermophysical Properties of Deep Eutectic Solvents by Data Integration

Abstract

Not specified

Authors: Xinmeng Xu, Jan Range, Gudrun Gygli, Jürgen Pleiss

Date Published: 12th Mar 2020

Publication Type: Journal

The emergence of a novel coronavirus (SARS-CoV-2), their biology and therapeutic options

Abstract (Expand)

The new decade of the 21 st century (2020) started with the emergence of novel coronavirus known as SARS-CoV-2 that caused an epidemic of coronavirus disease (COVID-19) in Wuhan, China. It is the third … highly pathogenic and transmissible coronavirus after severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV) emerged in humans. The source of origin, transmission to humans and mechanisms associated with the pathogenicity of SARS-CoV-2 are not clear yet, however, its resemblance with SARS-CoV and several other bat coronaviruses was recently confirmed through genome sequencing related studies. The development of therapeutic strategies is necessary in order to prevent further epidemics and cure infected people. In this Review, we summarize current information about the emergence, origin, diversity, and epidemiology of three pathogenic coronaviruses with a specific focus on the current outbreak in Wuhan, China. Furthermore, we discuss the clinical features and potential therapeutic options that may be effective against SARS-CoV-2.

Authors: Suliman Khan, Rabeea Siddique, Muhammad Adnan Shereen, Ashaq Ali, Jianbo Liu, Qian Bai, Nadia Bashir, Mengzhou Xue

Date Published: 11th Mar 2020

Publication Type: Journal

Repurposing Therapeutics for COVID-19: Supercomputer-Based Docking to the SARS-CoV-2 Viral Spike Protein and Viral Spike Protein-Human ACE2 Interface

Abstract

Not specified

Authors: Micholas Smith, Jeremy C. Smith

Date Published: 11th Mar 2020

Publication Type: Journal

SARS-CoV-2 is sensitive to type I interferon pretreatment

Abstract (Expand)

Abstract SARS-CoV-2, a novel coronavirus (CoV), has recently emerged causing an ongoing outbreak of viral pneumonia around the world. While genetically distinct from the original SARS-CoV, both group … 2B CoVs share similar genome organization and origins to coronaviruses harbored in bats. Importantly, initial guidance has used insights from SARS-CoV infection to inform treatment and public health strategies. In this report, we evaluate type-I Interferon (IFN-I) sensitivity of SARS-CoV-2 relative to the original SARS-CoV. Our results indicate that while SARS-CoV-2 maintains similar viral replication kinetics to SARS-CoV in Vero cell, the novel CoV is much more sensitive to IFN-I pretreatment. Examining transcriptional factor activation and interferon stimulated gene (ISG) induction, SARS-CoV-2 in the context of type I IFN induces phosphorylation of STAT1 and increased ISG proteins. In contrast, the original SARS-CoV has no evidence for STAT1 phosphorylation or ISG protein increases even in the presence of type I IFN pretreatment. Finally, we examined homology between SARS-CoV and SARS-CoV-2 in viral proteins shown to be interferon antagonist. The absence of open reading frame (ORF) 3b and significant changes to ORF6 suggest the two key IFN antagonists may not maintain equivalent function in SARS-CoV-2. Together, the results identify key differences in susceptibility to the IFN-I response between SARS-CoV and SARS-CoV-2. that could help inform disease progression, treatment options, and animal model development. Importance With the ongoing outbreak of COVID-19 disease, differences between the SARS-CoV-2 and the original SARS-CoV could be leveraged to inform disease progression and eventual treatment options. In addition, these findings could have key implications for animal model development as well as further research into how SARS-CoV-2 modulates the type I IFN response early during infection. Article Summary SARS-CoV-2 has similar replication kinetics to SARS-CoV, but demonstrates significant sensitivity to type I interferon treatment.

Authors: Kumari G. Lokugamage, Adam Hage, Craig Schindewolf, Ricardo Rajsbaum, Vineet D. Menachery

Date Published: 9th Mar 2020

Publication Type: Tech report

Exploring diseases/traits and blood proteins causally related to expression of ACE2, the putative receptor of 2019-nCov: A Mendelian Randomization analysis

Abstract (Expand)

The novel coronavirus 2019-nCoV has caused major outbreaks in many parts of the world. A better understanding of the pathophysiology of COVID-19 is urgently needed. Clinically, it is important to … identify who may be susceptible to infection and identify treatments for the disease.

Authors: Shitao Rao, Alexandria Lau, Hon-Cheong So

Date Published: 8th Mar 2020

Publication Type: Tech report

LY6E impairs coronavirus fusion and confers immune control of viral disease

Abstract (Expand)

Zoonotic coronaviruses (CoVs) are significant threats to global health, as exemplified by the recent emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)1. Host immune responses … to CoV are complex and regulated in part through antiviral interferons. However, the interferon-stimulated gene products that inhibit CoV are not well characterized2. Here, we show that interferon-inducible lymphocyte antigen 6 complex, locus E (LY6E) potently restricts cellular infection by multiple CoVs, including SARS-CoV, SARS-CoV-2, and Middle East respiratory syndrome coronavirus (MERS-CoV). Mechanistic studies revealed that LY6E inhibits CoV entry into cells by interfering with spike protein-mediated membrane fusion. Importantly, mice lacking Ly6e in hematopoietic cells were highly susceptible to murine CoV infection. Exacerbated viral pathogenesis in Ly6e knockout mice was accompanied by loss of hepatic and splenic immune cells and reduction in global antiviral gene pathways. Accordingly, we found that Ly6e directly protects primary B cells and dendritic cells from murine CoV infection. Our results demonstrate that LY6E is a critical antiviral immune effector that controls CoV infection and pathogenesis. These findings advance our understanding of immune-mediated control of CoV in vitro and in vivo, knowledge that could help inform strategies to combat infection by emerging CoV.

Authors: Stephanie Pfaender, Katrina B. Mar, Eleftherios Michailidis, Annika Kratzel, Dagny Hirt, Philip V’kovski, Wenchun Fan, Nadine Ebert, Hanspeter Stalder, Hannah Kleine-Weber, Markus Hoffmann, H. Heinrich Hoffmann, Mohsan Saeed, Ronald Dijkman, Eike Steinmann, Mary Wight-Carter, Natasha W. Hanners, Stefan Pöhlmann, Tom Gallagher, Daniel Todt, Gert Zimmer, Charles M. Rice, John W. Schoggins, Volker Thiel

Date Published: 7th Mar 2020

Publication Type: Tech report

Understanding SARS-CoV-2-Mediated Inflammatory Responses: From Mechanisms to Potential Therapeutic Tools

Abstract (Expand)

Currently there is no effective antiviral therapy for SARS-CoV-2 infection, which frequently leads to fatal inflammatory responses and acute lung injury. Here, we discuss the various mechanisms of … SARS-CoV-mediated inflammation. We also assume that SARS-CoV-2 likely shares similar inflammatory responses. Potential therapeutic tools to reduce SARS-CoV-2 -induced inflammatory responses include various methods to block FcR activation. In the absence of a proven clinical FcR blocker, the use of intravenous immunoglobulin to block FcR activation may be a viable option for the urgent treatment of pulmonary inflammation to prevent severe lung injury. Such treatment may also be combined with systemic anti-inflammatory drugs or corticosteroids. However, these strategies, as proposed here, remain to be clinically tested for effectiveness.

Authors: Yajing Fu, Yuanxiong Cheng, Yuntao Wu

Date Published: 3rd Mar 2020

Publication Type: Journal

Mutations, Recombination and Insertion in the Evolution of 2019-nCoV

Abstract (Expand)

Background: The 2019 novel coronavirus (2019-nCoV or SARS-CoV-2) has spread more rapidly than any other betacoronavirus including SARS-CoV and MERS-CoV. However, the mechanisms responsible for infection … and molecular evolution of this virus 5 remained unclear. Methods: We collected and analyzed 120 genomic sequences of 2019-nCoV including 11 novel genomes from patients in China. Through comprehensive analysis of the available genome sequences of 2019-nCoV strains, we have tracked multiple inheritable SNPs and determined the evolution of 2019-nCoV relative to other 10 coronaviruses. Results: Systematic analysis of 120 genomic sequences of 2019-nCoV revealed cocirculation of two genetic subgroups with distinct SNPs markers, which can be used to trace the 2019-nCoV spreading pathways to different regions and countries. Although 2019-nCoV, human and bat SARS-CoV share high homologous in overall genome 15 structures, they evolved into two distinct groups with different receptor entry specificities through potential recombination in the receptor binding regions. In addition, 2019-nCoV has a unique four amino acid insertion between S1 and S2 domains of the spike protein, which created a potential furin or TMPRSS2 cleavage site. Conclusions: Our studies provided comprehensive insights into the evolution and 20

Authors: Aiping Wu, Peihua Niu, Lulan Wang, Hangyu Zhou, Xiang Zhao, Wenling Wang, Jingfeng Wang, Chengyang Ji, Xiao Ding, Xianyue Wang, Roujian Lu, Sarah Gold, Saba Aliyari, Shilei Zhang, Ellee Vikram, Angela Zou, Emily Lenh, Janet Chen, Fei Ye, Na Han, Yousong Peng, Haitao Guo, Guizhen Wu, Taijiao Jiang, Wenjie Tan, Genhong Cheng

Date Published: 2nd Mar 2020

Publication Type: Tech report

SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor

Abstract (Expand)

The recent emergence of the novel, pathogenic SARS-coronavirus 2 (SARS-CoV-2) in China and its rapid national and international spread pose a global health emergency. Cell entry of coronaviruses depends … on binding of the viral spike (S) proteins to cellular receptors and on S protein priming by host cell proteases. Unravelling which cellular factors are used by SARS-CoV-2 for entry might provide insights into viral transmission and reveal therapeutic targets. Here, we demonstrate that SARS-CoV-2 uses the SARS-CoV receptor ACE2 for entry and the serine protease TMPRSS2 for S protein priming. A TMPRSS2 inhibitor approved for clinical use blocked entry and might constitute a treatment option. Finally, we show that the sera from convalescent SARS patients cross-neutralized SARS-2S-driven entry. Our results reveal important commonalities between SARS-CoV-2 and SARS-CoV infection and identify a potential target for antiviral intervention.

Authors: Markus Hoffmann, Hannah Kleine-Weber, Simon Schroeder, Nadine Krüger, Tanja Herrler, Sandra Erichsen, Tobias S. Schiergens, Georg Herrler, Nai-Huei Wu, Andreas Nitsche, Marcel A. Müller, Christian Drosten, Stefan Pöhlmann

Date Published: 1st Mar 2020

Publication Type: Journal

Evidence for gastrointestinal infection of SARS-CoV-2

Abstract

Not specified

Authors: Fei Xiao, Meiwen Tang, Xiaobin Zheng, Ye Liu, Xiaofeng Li, Hong Shan

Date Published: 1st Mar 2020

Publication Type: Journal

Molecular immune pathogenesis and diagnosis of COVID-19

Abstract

Not specified

Authors: Xiaowei Li, Manman Geng, Yizhao Peng, Liesu Meng, Shemin Lu

Date Published: 1st Mar 2020

Publication Type: Journal

Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study

Abstract (Expand)

Background Since December, 2019, Wuhan, China, has experienced an outbreak of coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Epidemiological … and clinical characteristics of patients with COVID-19 have been reported but risk factors for mortality and a detailed clinical course of illness, including viral shedding, have not been well described.

Authors: Fei Zhou, Ting Yu, Ronghui Du, Guohui Fan, Ying Liu, Zhibo Liu, Jie Xiang, Yeming Wang, Bin Song, Xiaoying Gu, Lulu Guan, Yuan Wei, Hui Li, Xudong Wu, Jiuyang Xu, Shengjin Tu, Yi Zhang, Hua Chen, Bin Cao

Date Published: 1st Mar 2020

Publication Type: Journal

Identification of a 2,4-diaminopyrimidine scaffold targeting Trypanosoma brucei pteridine reductase 1 from the LIBRA compound library screening campaign.

Abstract (Expand)

The LIBRA compound library is a collection of 522 non-commercial molecules contributed by various Italian academic laboratories. These compounds have been designed and synthesized during different … medicinal chemistry programs and are hosted by the Italian Institute of Technology. We report the screening of the LIBRA compound library against Trypanosoma brucei and Leishmania major pteridine reductase 1, TbPTR1 and LmPTR1. Nine compounds were active against parasitic PTR1 and were selected for cell-based parasite screening, as single agents and in combination with methotrexate (MTX). The most interesting TbPTR1 inhibitor identified was 4-(benzyloxy)pyrimidine-2,6-diamine (LIB_66). Subsequently, six new LIB_66 derivatives were synthesized to explore its Structure-Activity-Relationship (SAR) and absorption, distribution, metabolism, excretion and toxicity (ADMET) properties. The results indicate that PTR1 has a preference to bind inhibitors, which resemble its biopterin/folic acid substrates, such as the 2,4-diaminopyrimidine derivatives.

Authors: P. Linciano, G. Cullia, C. Borsari, M. Santucci, S. Ferrari, G. Witt, S. Gul, M. Kuzikov, B. Ellinger, N. Santarem, A. Cordeiro da Silva, P. Conti, M. L. Bolognesi, M. Roberti, F. Prati, F. Bartoccini, M. Retini, G. Piersanti, A. Cavalli, L. Goldoni, S. M. Bertozzi, F. Bertozzi, E. Brambilla, V. Rizzo, D. Piomelli, A. Pinto, T. Bandiera, M. P. Costi

Date Published: 1st Mar 2020

Publication Type: Journal

Clinical Characteristics of Coronavirus Disease 2019 in China

Abstract (Expand)

BACKGROUND Since December 2019, when coronavirus disease 2019 (Covid-19) emerged in Wuhan city and rapidly spread throughout China, data have been needed on the clinical characteristics of the affected … patients. METHODS We extracted data regarding 1099 patients with laboratory-confirmed Covid-19 from 552 hospitals in 30 provinces, autonomous regions, and municipalities in mainland China through January 29, 2020. The primary composite end point was admission to an intensive care unit (ICU), the use of mechanical ventilation, or death. The authors’ full names, academic degrees, and affiliations are listed in the Appendix. Address reprint requests to Dr. Zhong at the State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, First Affiliated Hospital of Guangzhou Medical University, 151 Yanjiang Rd., Guangzhou, Guangdong, China, or at ­nanshan@­vip.­163.­com. RESULTS The median age of the patients was 47 years; 41.9% of the patients were female. The primary composite end point occurred in 67 patients (6.1%), including 5.0% who were admitted to the ICU, 2.3% who underwent invasive mechanical ventilation, and 1.4% who died. Only 1.9% of the patients had a history of direct contact with wildlife. Among nonresidents of Wuhan, 72.3% had contact with residents of Wuhan, including 31.3% who had visited the city. The most common symptoms were fever (43.8% on admission and 88.7% during hospitalization) and cough (67.8%). Diarrhea was uncommon (3.8%). The median incubation period was 4 days (interquartile range, 2 to 7). On admission, ground-glass opacity was the most common radiologic finding on chest computed tomography (CT) (56.4%). No radiographic or CT abnormality was found in 157 of 877 patients (17.9%) with nonsevere disease and in 5 of 173 patients (2.9%) with severe disease. Lymphocytopenia was present in 83.2% of the patients on admission. *A list of investigators in the China Medical Treatment Expert Group for Covid-19 study is provided in the Supplementary Appendix, available at NEJM.org. Drs. Guan, Ni, Yu Hu, W. Liang, Ou, He, L. Liu, Shan, Lei, Hui, Du, L. Li, Zeng, and Yuen contributed equally to this article. This article was published on February 28, 2020, and last updated on March 6, 2020, at NEJM.org. DOI: 10.1056/NEJMoa2002032 Copyright © 2020 Massachusetts Medical Society. CONCLUSIONS During the first 2 months of the current outbreak, Covid-19 spread rapidly throughout China and caused varying degrees of illness. Patients often presented without fever, and many did not have abnormal radiologic findings. (Funded by the National Health Commission of China and others.)

Authors: Wei-jie Guan, Zheng-yi Ni, Yu Hu, Wen-hua Liang, Chun-quan Ou, Jian-xing He, Lei Liu, Hong Shan, Chun-liang Lei, David S.C. Hui, Bin Du, Lan-juan Li, Guang Zeng, Kwok-Yung Yuen, Ru-chong Chen, Chun-li Tang, Tao Wang, Ping-yan Chen, Jie Xiang, Shi-yue Li, Jin-lin Wang, Zi-jing Liang, Yi-xiang Peng, Li Wei, Yong Liu, Ya-hua Hu, Peng Peng, Jian-ming Wang, Ji-yang Liu, Zhong Chen, Gang Li, Zhi-jian Zheng, Shao-qin Qiu, Jie Luo, Chang-jiang Ye, Shao-yong Zhu, Nan-shan Zhong

Date Published: 28th Feb 2020

Publication Type: Journal

The landscape of lung bronchoalveolar immune cells in COVID-19 revealed by single-cell RNA sequencing

Abstract (Expand)

The novel coronavirus SARS-CoV-2, etiological agent of recently named Coronavirus infected disease (COVID-19) by WHO, has caused more than 2, 000 deaths worldwide since its emergency in Wuhan City, … Hubei province, China, in December, 2019. The symptoms of COVID-19 varied from modest, mild to acute respiratory distress syndrome (ARDS), and the latter of which is generally associated with deregulated immune cytokine production; however, we currently know little as to the interplay between the extent of clinical symptoms and the compositions of lung immune microenvironment. Here, we comprehensively characterized the lung immune microenvironment with the bronchoalveolar lavage fluid (BALF) from 3 severe and 3 mild COVID-19 patients and 8 previously reported healthy lung controls through single-cell RNA sequence (scRNA-seq) combined with TCR-seq. Our data shows that monocyte-derived FCN1+ macrophages, whereas notFABP4+ alveolar macrophages that represent a predominant macrophage subset in BALF from patients with mild diseases, overwhelm in the severely damaged lungs from patients with ARDS. These cells are highly inflammatory and enormous chemokine producers implicated in cytokine storm. Furthermore, the formation of tissue resident, highly expanded clonal CD8+ T cells in the lung microenvironment of mild symptom patients suggests a robust adaptive immune response connected to a better control of COVID-19. This study first reported the cellular atlas of lung bronchoalveolar immune microenvironment in COVID-19 patients at the single-cell resolution, and unveiled the potential immune mechanisms underlying disease progression and protection in COVID-19.

Authors: Minfeng Liao, Yang Liu, Jin Yuan, Yanling Wen, Gang Xu, Juanjuan Zhao, Lin Chen, Jinxiu Li, Xin Wang, Fuxiang Wang, Lei Liu, Shuye Zhang, Zheng Zhang

Date Published: 26th Feb 2020

Publication Type: Tech report

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