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

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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

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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

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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

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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

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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

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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

Clinical Characteristics of Coronavirus Disease 2019 in China

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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

Genomic variance of the 2019-nCoV coronavirus

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There is a rising global concern for the recently emerged novel coronavirus (2019-nCoV). Full genomic sequences have been released by the worldwide scientific community in the last few weeks to understand … the evolutionary origin and molecular characteristics of this virus. Taking advantage of all the genomic information currently available, we constructed a phylogenetic tree including also representatives of other coronaviridae, such as Bat coronavirus (BCoV) and severe acute respiratory syndrome. We confirm high sequence similarity (\textgreater99%) between all sequenced 2019-nCoVs genomes available, with the closest BCoV sequence sharing 96.2% sequence identity, confirming the notion of a zoonotic origin of 2019-nCoV. Despite the low heterogeneity of the 2019-nCoV genomes, we could identify at least two hypervariable genomic hotspots, one of which is responsible for a Serine/Leucine variation in the viral ORF8-encoded protein. Finally, we perform a full proteomic comparison with other coronaviridae, identifying key aminoacidic differences to be considered for antiviral strategies deriving from previous anti-coronavirus approaches.

Authors: Carmine Ceraolo, Federico M. Giorgi

Date Published: 24th Feb 2020

Publication Type: Journal

Furin, a potential therapeutic target for COVID-19

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A novel coronavirus (SARS-CoV-2) infectious disease has broken out in Wuhan, Hubei Province since December 2019, and spread rapidly from Wuhan to other areas, which has been listed as an international … concerning public health emergency. We compared the Spike proteins from four sources, SARS-CoV-2, SARS-CoV, MERS-CoV and Bat-CoVRaTG13, and found that the SARS-CoV-2 virus sequence had redundant PRRA sequences. Through a series of analyses, we propose the reason why SARS-CoV-2is more infectious than other coronaviruses. And through structure based virtual ligand screening, we foundpotentialfurin inhibitors, which might be used in the treatment of new coronary pneumonia.

Authors: Canrong Wu, Yueying Yang, Yang Liu, Peng Zhang, Yali Wang, Hua Li, Qiqi Wang, Yang Xu, Mingxue Li, Mengzhu Zheng, Lixia Chen

Date Published: 23rd Feb 2020

Publication Type: Journal

Structure, function and antigenicity of the SARS-CoV-2 spike glycoprotein

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SUMMARY The recent emergence of a novel coronavirus associated with an ongoing outbreak of pneumonia (Covid-2019) resulted in infections of more than 72,000 people and claimed over 1,800 lives. Coronavirus … spike (S) glycoprotein trimers promote entry into cells and are the main target of the humoral immune response. We show here that SARS-CoV-2 S mediates entry in VeroE6 cells and in BHK cells transiently transfected with human ACE2, establishing ACE2 as a functional receptor for this novel coronavirus. We further demonstrate that the receptor-binding domains of SARS-CoV-2 S and SARS-CoV S bind with similar affinities to human ACE2, which correlates with the efficient spread of SARS-CoV-2 among humans. We found that the SARS-CoV-2 S glycoprotein harbors a furin cleavage site at the boundary between the S 1 /S 2 subunits, which is processed during biogenesis and sets this virus apart from SARS-CoV and other SARS-related CoVs. We determined a cryo-electron microscopy structure of the SARS-CoV-2 S ectodomain trimer, demonstrating spontaneous opening of the receptor-binding domain, and providing a blueprint for the design of vaccines and inhibitors of viral entry. Finally, we demonstrate that SARS-CoV S murine polyclonal sera potently inhibited SARS-CoV-2 S-mediated entry into target cells, thereby indicating that cross-neutralizing antibodies targeting conserved S epitopes can be elicited upon vaccination.

Authors: Alexandra C. Walls, Young-Jun Park, M. Alexandra Tortorici, Abigail Wall, Andrew T. McGuire, David Veesler

Date Published: 20th Feb 2020

Publication Type: Tech report

Reduction and Functional Exhaustion of T Cells in Patients with Coronavirus Disease 2019 (COVID-19)

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BACKGROUND The outbreak of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has posed great threat to human health, which has been declared a … public health emergency of international concern (PHEIC) by the WHO. T cells play a critical role in antiviral immunity but their numbers and functional state in COVID-19 patients remain largely unclear. METHODS We retrospectively reviewed the counts of total T cells, CD4+, CD8+ T cell subsets, and serum cytokine concentration from inpatient data of 522 patients with laboratory-confirmed COVID-19, admitted into two hospitals in Wuhan from December 2019 to January 2020, and 40 healthy controls, who came to the hospitals for routine physical examination. In addition, the expression of T cell exhaustion markers PD-1 and Tim-3 were measured by flow cytometry in the peripheral blood of 14 COVID-19 cases. RESULTS The number of total T cells, CD4+ and CD8+ T cells were dramatically reduced in COVID-19 patients, especially among elderly patients (≥60 years of age) and in patients requiring Intensive Care Unit (ICU) care. Counts of total T cells, CD8+T cells or CD4+T cells lower than 800/μL, 300/μL, or 400/μL, respectively, are negatively correlated with patient survival. Statistical analysis demonstrated that T cell numbers are negatively correlated to serum IL-6, IL-10 and TNF-α concentration, with patients in decline period showing reduced IL-6, IL-10 and TNF-α concentrations and restored T cell counts. Finally, T cells from COVID-19 patients have significantly higher levels of the exhausted marker PD-1 as compared to health controls. Moreover, increasing PD-1 and Tim-3 expression on T cells could be seen as patients progressed from prodromal to overtly symptomatic stages, further indicative of T cell exhaustion. CONCLUSIONS T cell counts are reduced significantly in COVID-19 patients, and the surviving T cells appear functionally exhausted. Non-ICU patients, with total T cells, CD8+T cells CD4+T cells counts lower than 800/μL, 300/μL, and 400/μL, respectively, may still require aggressive intervention even in the immediate absence of more severe symptoms due to a high risk for further deterioration in condition.

Authors: Bo Diao, Chenhui Wang, Yingjun Tan, Xiewan Chen, Ying Liu, Lifeng Ning, Li Chen, Min Li, Yueping Liu, Gang Wang, Zilin Yuan, Zeqing Feng, Yuzhang Wu, Yongwen Chen

Date Published: 20th Feb 2020

Publication Type: Tech report

NLRP3 Inflammasome-A Key Player in Antiviral Responses

Abstract (Expand)

The NACHT, LRR, and PYD domains-containing protein 3 (NLRP3) inflammasome is an oligomeric complex comprised of the NOD-like receptor NLRP3, the adaptor ASC, and caspase-1. This complex is crucial to … the host’s defense against microbes as it promotes IL-1β and IL-18 secretion and induces pyroptosis. NLRP3 recognizes variety of pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs) generated during viral replication that triggers the NLRP3 inflammasome-dependent antiviral immune responses and facilitates viral eradication. Meanwhile, several viruses have evolved elaborate strategies to evade the immune system by targeting the NLRP3 inflammasome. In this review, we will focus on the crosstalk between the NLRP3 inflammasome and viruses, provide an overview of viral infection-induced NLRP3 inflammasome activation, and the immune escape strategies of viruses through their modulation of the NLRP3 inflammasome activity.

Authors: Chunyuan Zhao, Wei Zhao

Date Published: 18th Feb 2020

Publication Type: Journal

The insert sequence in SARS-CoV-2 enhances spike protein cleavage by TMPRSS

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Abstract At the end of 2019, the SARS-CoV-2 induces an ongoing outbreak of pneumonia in China 1 , even more spread than SARS-CoV infection 2 . The entry of SARS-CoV into host cells mainly depends on … the cell receptor (ACE2) recognition and spike protein cleavage-induced cell membrane fusion 3,4 . The spike protein of SARS-CoV-2 also binds to ACE2 with a similar affinity, whereas its spike protein cleavage remains unclear 5,6 . Here we show that an insertion sequence in the spike protein of SARS-CoV-2 enhances the cleavage efficiency, and besides pulmonary alveoli, intestinal and esophagus epithelium were also the target tissues of SARS-CoV-2. Compared with SARS-CoV, we found a SPRR insertion in the S1/S2 protease cleavage sites of SARS-CoV-2 spike protein increasing the cleavage efficiency by the protein sequence aligment and furin score calculation. Additionally, the insertion sequence facilitates the formation of an extended loop which was more suitable for protease recognition by the homology modeling and molicular docking. Furthermore, the single-cell transcriptomes identified that ACE2 and TMPRSSs are highly coexpressed in AT2 cells of lung, along with esophageal upper epithelial cells and absorptive enterocytes. Our results provide the bioinformatics evidence for the increased spike protein cleavage of SARS-CoV-2 and indicate its potential target cells.

Authors: Tong Meng, Hao Cao, Hao Zhang, Zijian Kang, Da Xu, Haiyi Gong, Jing Wang, Zifu Li, Xingang Cui, Huji Xu, Haifeng Wei, Xiuwu Pan, Rongrong Zhu, Jianru Xiao, Wang Zhou, Liming Cheng, Jianmin Liu

Date Published: 11th Feb 2020

Publication Type: Tech report

Clinical characteristics of 2019 novel coronavirus infection in China

Abstract (Expand)

Background: Since December 2019, acute respiratory disease (ARD) due to 2019 novel coronavirus (2019-nCoV) emerged in Wuhan city and rapidly spread throughout China. We sought to delineate the clinical … characteristics of these cases.

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 SC Hui, Bin Du, Lan-juan Li, Guang Zeng, Kowk-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: 9th Feb 2020

Publication Type: Tech report

Emerging coronaviruses: Genome structure, replication, and pathogenesis

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The recent emergence of a novel coronavirus (2019‐nCoV), which is causing an outbreak of unusual viral pneumonia in patients in Wuhan, a central city in China, is another warning of the risk of CoVs … posed to public health. In this minireview, we provide a brief introduction of the general features of CoVs and describe diseases caused by different CoVs in humans and animals. This review will help understand the biology and potential risk of CoVs that exist in richness in wildlife such as bats.

Authors: Yu Chen, Qianyun Liu, Deyin Guo

Date Published: 7th Feb 2020

Publication Type: Journal

Coronavirus infections and immune responses

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Coronaviruses (CoVs) are by far the largest group of known positive-sense RNA viruses having an extensive range of natural hosts. In the past few decades, newly evolved Coronaviruses have posed a global … threat to public health. The immune response is essential to control and eliminate CoV infections, however, maladjusted immune responses may result in immunopathology and impaired pulmonary gas exchange. Gaining a deeper understanding of the interaction between Coronaviruses and the innate immune systems of the hosts may shed light on the development and persistence of inflammation in the lungs and hopefully can reduce the risk of lung inflammation caused by CoVs. In this review, we provide an update on CoV infections and relevant diseases, particularly the host defense against CoV-induced inflammation of lung tissue, as well as the role of the innate immune system in the pathogenesis and clinical treatment.

Authors: Geng Li, Yaohua Fan, Yanni Lai, Tiantian Han, Zonghui Li, Peiwen Zhou, Pan Pan, Wenbiao Wang, Dingwen Hu, Xiaohong Liu, Qiwei Zhang, Jianguo Wu

Date Published: 7th Feb 2020

Publication Type: Journal

Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China

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Background A recent cluster of pneumonia cases in Wuhan, China, was caused by a novel betacoronavirus, the 2019 novel coronavirus (2019-nCoV). We report the epidemiological, clinical, laboratory, and … radiological characteristics and treatment and clinical outcomes of these patients.

Authors: Chaolin Huang, Yeming Wang, Xingwang Li, Lili Ren, Jianping Zhao, Yi Hu, Li Zhang, Guohui Fan, Jiuyang Xu, Xiaoying Gu, Zhenshun Cheng, Ting Yu, Jiaan Xia, Yuan Wei, Wenjuan Wu, Xuelei Xie, Wen Yin, Hui Li, Min Liu, Yan Xiao, Hong Gao, Li Guo, Jungang Xie, Guangfa Wang, Rongmeng Jiang, Zhancheng Gao, Qi Jin, Jianwei Wang, Bin Cao

Date Published: 1st Feb 2020

Publication Type: Journal

A tug-of-war between severe acute respiratory syndrome coronavirus 2 and host antiviral defence: lessons from other pathogenic viruses

Abstract (Expand)

World Health Organization has declared the ongoing outbreak of coronavirus disease 2019 (COVID-19) a Public Health Emergency of International Concern. The virus was named severe acute respiratory … syndrome coronavirus 2 (SARSCoV-2) by the International Committee on Taxonomy of Viruses. Human infection with SARS-CoV-2 leads to a wide range of clinical manifestations ranging from asymptomatic, mild, moderate to severe. The severe cases present with pneumonia, which can progress to acute respiratory distress syndrome. The outbreak provides an opportunity for real-time tracking of an animal coronavirus that has just crossed species barrier to infect humans. The outcome of SARS-CoV-2 infection is largely determined by virus-host interaction. Here, we review the discovery, zoonotic origin, animal hosts, transmissibility and pathogenicity of SARS-CoV-2 in relation to its interplay with host antiviral defense. A comparison with SARS-CoV, Middle East respiratory syndrome coronavirus, community-acquired human coronaviruses and other pathogenic viruses including human immunodeficiency viruses is made. We summarize current understanding of the induction of a proinflammatory cytokine storm by other highly pathogenic human coronaviruses, their adaptation to humans and their usurpation of the cell death programmes. Important questions concerning the interaction between SARS-CoV-2 and host antiviral defence, including asymptomatic and presymptomatic virus shedding, are also discussed.

Authors: Sin-Yee Fung, Kit-San Yuen, Zi-Wei Ye, Chi-Ping Chan, Dong-Yan Jin

Date Published: 2020

Publication Type: Journal

Genomic characterization of the 2019 novel human-pathogenic coronavirus isolated from a patient with atypical pneumonia after visiting Wuhan

Abstract (Expand)

A mysterious outbreak of atypical pneumonia in late 2019 was traced to a seafood wholesale market in Wuhan of China. Within a few weeks, a novel coronavirus tentatively named as 2019 novel coronavirus … (2019-nCoV) was announced by the World Health Organization. We performed bioinformatics analysis on a virus genome from a patient with 2019-nCoV infection and compared it with other related coronavirus genomes. Overall, the genome of 2019-nCoV has 89% nucleotide identity with bat SARS-like-CoVZXC21 and 82% with that of human SARS-CoV. The phylogenetic trees of their orf1a/b, Spike, Envelope, Membrane and Nucleoprotein also clustered closely with those of the bat, civet and human SARS coronaviruses. However, the external subdomain of Spike’s receptor binding domain of 2019-nCoV shares only 40% amino acid identity with other SARS-related coronaviruses. Remarkably, its orf3b encodes a completely novel short protein. Furthermore, its new orf8 likely encodes a secreted protein with an alpha-helix, following with a beta-sheet(s) containing six strands. Learning from the roles of civet in SARS and camel in MERS, hunting for the animal source of 2019-nCoV and its more ancestral virus would be important for understanding the origin and evolution of this novel lineage B betacoronavirus. These findings provide the basis for starting further studies on the pathogenesis, and optimizing the design of diagnostic, antiviral and vaccination strategies for this emerging infection.

Authors: Jasper Fuk-Woo Chan, Kin-Hang Kok, Zheng Zhu, Hin Chu, Kelvin Kai-Wang To, Shuofeng Yuan, Kwok-Yung Yuen

Date Published: 2020

Publication Type: Journal

Targeting the Endocytic Pathway and Autophagy Process as a Novel Therapeutic Strategy in COVID-19

Abstract (Expand)

Coronaviruses (CoVs) are a group of enveloped, single-stranded positive genomic RNA viruses and some of them are known to cause severe respiratory diseases in human, including Severe Acute Respiratory … Syndrome (SARS), Middle East Respiratory Syndrome (MERS) and the ongoing coronavirus disease-19 (COVID-19). One key element in viral infection is the process of viral entry into the host cells. In the last two decades, there is increasing understanding on the importance of the endocytic pathway and the autophagy process in viral entry and replication. As a result, the endocytic pathway including endosome and lysosome has become important targets for development of therapeutic strategies in combating diseases caused by CoVs. In this mini-review, we will focus on the importance of the endocytic pathway as well as the autophagy process in viral infection of several pathogenic CoVs inclusive of SARS-CoV, MERS-CoV and the new CoV named as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and discuss the development of therapeutic agents by targeting these processes. Such knowledge will provide important clues for control of the ongoing epidemic of SARS-CoV-2 infection and treatment of COVID-19.

Authors: Naidi Yang, Han-Ming Shen

Date Published: 2020

Publication Type: Journal

Data Management in Computational Systems Biology: Exploring Standards, Tools, Databases, and Packaging Best Practices.

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Computational systems biology involves integrating heterogeneous datasets in order to generate models. These models can assist with understanding and prediction of biological phenomena. Generating … datasets and integrating them into models involves a wide range of scientific expertise. As a result these datasets are often collected by one set of researchers, and exchanged with others researchers for constructing the models. For this process to run smoothly the data and models must be FAIR-findable, accessible, interoperable, and reusable. In order for data and models to be FAIR they must be structured in consistent and predictable ways, and described sufficiently for other researchers to understand them. Furthermore, these data and models must be shared with other researchers, with appropriately controlled sharing permissions, before and after publication. In this chapter we explore the different data and model standards that assist with structuring, describing, and sharing. We also highlight the popular standards and sharing databases within computational systems biology.

Authors: N. J. Stanford, M. Scharm, P. D. Dobson, M. Golebiewski, M. Hucka, V. B. Kothamachu, D. Nickerson, S. Owen, J. Pahle, U. Wittig, D. Waltemath, C. Goble, P. Mendes, J. Snoep

Date Published: 12th Oct 2019

Publication Type: Journal

Human Coronavirus: Host-Pathogen Interaction

Abstract (Expand)

Human coronavirus (HCoV) infection causes respiratory diseases with mild to severe outcomes. In the last 15 years, we have witnessed the emergence of two zoonotic, highly pathogenic HCoVs: severe acute … respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV). Replication of HCoV is regulated by a diversity of host factors and induces drastic alterations in cellular structure and physiology. Activation of critical signaling pathways during HCoV infection modulates the induction of antiviral immune response and contributes to the pathogenesis of HCoV. Recent studies have begun to reveal some fundamental aspects of the intricate HCoV-host interaction in mechanistic detail. In this review, we summarize the current knowledge of host factors co-opted and signaling pathways activated during HCoV infection, with an emphasis on HCoV-infection-induced stress response, autophagy, apoptosis, and innate immunity. The cross talk among these pathways, as well as the modulatory strategies utilized by HCoV, is also discussed.

Authors: To Sing Fung, Ding Xiang Liu

Date Published: 8th Sep 2019

Publication Type: Journal

Conceptual and computational framework for logical modelling of biological networks deregulated in diseases.

Abstract (Expand)

Mathematical models can serve as a tool to formalize biological knowledge from diverse sources, to investigate biological questions in a formal way, to test experimental hypotheses, to predict the … effect of perturbations and to identify underlying mechanisms. We present a pipeline of computational tools that performs a series of analyses to explore a logical model's properties. A logical model of initiation of the metastatic process in cancer is used as a transversal example. We start by analysing the structure of the interaction network constructed from the literature or existing databases. Next, we show how to translate this network into a mathematical object, specifically a logical model, and how robustness analyses can be applied to it. We explore the visualization of the stable states, defined as specific attractors of the model, and match them to cellular fates or biological read-outs. With the different tools we present here, we explain how to assign to each solution of the model a probability and how to identify genetic interactions using mutant phenotype probabilities. Finally, we connect the model to relevant experimental data: we present how some data analyses can direct the construction of the network, and how the solutions of a mathematical model can also be compared with experimental data, with a particular focus on high-throughput data in cancer biology. A step-by-step tutorial is provided as a Supplementary Material and all models, tools and scripts are provided on an accompanying website: https://github.com/sysbio-curie/Logical_modelling_pipeline.

Authors: A. Montagud, P. Traynard, L. Martignetti, E. Bonnet, E. Barillot, A. Zinovyev, L. Calzone

Date Published: 19th Jul 2019

Publication Type: Journal

Specifications of Standards in Systems and Synthetic Biology: Status and Developments in 2019

Abstract (Expand)

This special issue of the Journal of Integrative Bioinformatics presents an overview of COMBINE standards and their latest specifications. The standards cover representation formats for computational … modeling in synthetic and systems biology and include BioPAX, CellML, NeuroML, SBML, SBGN, SBOL and SED-ML. The articles in this issue contain updated specifications of SBGN Process Description Level 1 Version 2, SBML Level 3 Core Version 2 Release 2, SBOL Version 2.3.0, and SBOL Visual Version 2.1.

Authors: Falk Schreiber, Björn Sommer, Gary D. Bader, Padraig Gleeson, Martin Golebiewski, Michael Hucka, Sarah M. Keating, Matthias König, Chris Myers, David Nickerson, Dagmar Waltemath

Date Published: 13th Jul 2019

Publication Type: Journal

PhysiBoSS: a multi-scale agent-based modelling framework integrating physical dimension and cell signalling

Abstract

Not specified

Authors: Gaelle Letort, Arnau Montagud, Gautier Stoll, Randy Heiland, Emmanuel Barillot, Paul Macklin, Andrei Zinovyev, Laurence Calzone

Date Published: 1st Apr 2019

Publication Type: Journal

Harmonizing semantic annotations for computational models in biology

Abstract (Expand)

Life science researchers use computational models to articulate and test hypotheses about the behavior of biological systems. Semantic annotation is a critical component for enhancing the interoperability … and reusability of such models as well as for the integration of the data needed for model parameterization and validation. Encoded as machine-readable links to knowledge resource terms, semantic annotations describe the computational or biological meaning of what models and data represent. These annotations help researchers find and repurpose models, accelerate model composition and enable knowledge integration across model repositories and experimental data stores. However, realizing the potential benefits of semantic annotation requires the development of model annotation standards that adhere to a community-based annotation protocol. Without such standards, tool developers must account for a variety of annotation formats and approaches, a situation that can become prohibitively cumbersome and which can defeat the purpose of linking model elements to controlled knowledge resource terms. Currently, no consensus protocol for semantic annotation exists among the larger biological modeling community. Here, we report on the landscape of current annotation practices among the COmputational Modeling in BIology NEtwork community and provide a set of recommendations for building a consensus approach to semantic annotation.

Authors: Maxwell Lewis Neal, Matthias König, David Nickerson, Göksel Mısırlı, Reza Kalbasi, Andreas Dräger, Koray Atalag, Vijayalakshmi Chelliah, Michael T Cooling, Daniel L Cook, Sharon Crook, Miguel de Alba, Samuel H Friedman, Alan Garny, John H Gennari, Padraig Gleeson, Martin Golebiewski, Michael Hucka, Nick Juty, Chris Myers, Brett G Olivier, Herbert M Sauro, Martin Scharm, Jacky L Snoep, Vasundra Touré, Anil Wipat, Olaf Wolkenhauer, Dagmar Waltemath

Date Published: 1st Mar 2019

Publication Type: Journal

Severe Acute Respiratory Syndrome Coronavirus Viroporin 3a Activates the NLRP3 Inflammasome

Abstract

Not specified

Authors: I-Yin Chen, Miyu Moriyama, Ming-Fu Chang, Takeshi Ichinohe

Date Published: 29th Jan 2019

Publication Type: Journal

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