Rxivist combines preprints from bioRxiv with data from Twitter to help you find the papers being discussed in your field. Currently indexing 84,649 bioRxiv papers from 364,232 authors.
Most downloaded bioRxiv papers, since beginning of last month
82,567 results found. For more information, click each entry to expand.
2,915 downloads bioinformatics
The authors have withdrawn their manuscript whilst they wish to perform additional experiments to validate their conclusions further. Therefore, the authors do not wish this work to be cited as reference for the project. If you have any questions, please contact the corresponding author for more details. ### Competing Interest Statement The authors have declared no competing interest.
2,857 downloads pathology
Liqun He, Maarja Andaloussi Mäe, Ying Sun, Lars Muhl, Khayrun Nahar, Elisa Vázquez Liébanas, Malin Jonsson Fagerlund, Anders Oldner, Jianping Liu, Guillem Genové, Riikka Pietilä, Lei Zhang, Yuan Xie, Stefanos Leptidis, Guiseppe Mocci, Simon Stritt, Ahmed Osman, Andrey Anisimov, Karthik Amudhala Hemanthakumar, Markus Räsenen, Johan Björkegren, Michael Vanlandewijck, Klas Blomgren, Emil Hansson, Taija Mäkinen, Xiao-Rong Peng, Thomas D. Arnold, Kari Alitalo, Lars I Eriksson, Urban Lendahl, Christer Betsholtz
Accumulating clinical observations suggest pathogenesis beyond viral pneumonia and its secondary consequences in COVID-19 patients. In particular, many patients develop profound hyperinflammation and hypercoagulopathy with disseminated thrombogenesis and thromboembolism, which we observe also in a Swedish COVID-19 intensive care patient cohort. To understand these vascular manifestations, it is important to establish the potential vascular entry point(s) of the SARS-CoV-2 virus, i.e. which vascular cell types express the SARS-CoV-2 receptor ACE2. We present data that ACE2 is specifically and highly expressed in microvascular pericytes, but absent from endothelial cells, perivascular macrophages and fibroblasts. Mice with pericyte ablation show increased expression and release of Von Willebrand Factor from microvascular endothelial cells, suggesting that pericytes orchestrate thrombogenic responses in neighboring endothelial cells. Identifying pericytes rather than endothelial cells as the ACE2-expressing cells in the vasculature may explain why hypertension, diabetes and obesity are risk factors for severe COVID-19 patients, as these conditions are characterized by an impaired endothelial barrier function, allowing SARS-CoV-2 to reach and infect the pericytes that are normally shielded from the blood behind an intact endothelial barrier. This novel COVID-19-pericyte hypothesis is testable, offers explanations for some of the most enigmatic and lethal aspects of COVID-19 and calls for further investigations into the possible benefits of preventive anticoagulant therapy. ### Competing Interest Statement The authors have declared no competing interest.
2,770 downloads cancer biology
The U.S. National Toxicology Program (NTP) has carried out extensive rodent toxicology and carcinogenesis studies of radiofrequency radiation (RFR) at frequencies and modulations used in the U.S. telecommunications industry. This report presents partial findings from these studies. The occurrences of two tumor types in male Harlan Sprague Dawley rats exposed to RFR, malignant gliomas in the brain and schwannomas of the heart, were considered of particular interest and are the subject of this report. The findings in this report were reviewed by expert peer reviewers selected by the NTP and National Institutes of Health (NIH). These reviews and responses to comments are included as appendices to this report, and revisions to the current document have incorporated and addressed these comments. When the studies are completed, they will undergo additional peer review before publication in full as part of the NTP's Toxicology and Carcinogenesis Technical Reports Series. No portion of this work has been submitted for publication in a scientific journal. Supplemental information in the form of four additional manuscripts has or will soon be submitted for publication. These manuscripts describe in detail the designs and performance of the RFR exposure system, the dosimetry of RFR exposures in rats and mice, the results to a series of pilot studies establishing the ability of the animals to thermoregulate during RFR exposures, and studies of DNA damage. (1) Capstick M, Kuster N, Kuhn S, Berdinas-Torres V, Wilson P, Ladbury J, Koepke G, McCormick D, Gauger J, and Melnick R. A radio frequency radiation reverberation chamber exposure system for rodents; (2) Yijian G, Capstick M, McCormick D, Gauger J, Horn T, Wilson P, Melnick RL, and Kuster N. Life time dosimetric assessment for mice and rats exposed to cell phone radiation; (3) Wyde ME, Horn TL, Capstick M, Ladbury J, Koepke G, Wilson P, Stout MD, Kuster N, Melnick R, Bucher JR, and McCormick D. Pilot studies of the National Toxicology Program's cell phone radiofrequency radiation reverberation chamber exposure system; (4) Smith-Roe SL, Wyde ME, Stout MD, Winters J, Hobbs CA, Shepard KG, Green A, Kissling GE, Tice RR, Bucher JR, and Witt KL. Evaluation of the genotoxicity of cell phone radiofrequency radiation in male and female rats and mice following subchronic exposure.
2,724 downloads microbiology
Hongjing Gu, Qi Chen, Guan Yang, Lei He, Hang Fan, Yong-Qiang Deng, Yanxiao Wang, Yue Teng, Zhongpeng Zhao, Yujun Cui, Yuchang Li, Xiao-Feng Li, Jiangfan Li, Nana Zhang, Xiaolan Yang, Shaolong Chen, Guangyu Zhao, Xiliang Wang, Deyan Luo, Hui Wang, Xiao Yang, Yan Li, Gencheng Han, Yuxian He, Xiaojun Zhou, Shusheng Geng, Xiaoli Sheng, Shibo Jiang, Shihui Sun, Cheng-Feng Qin, Yusen Zhou
Coronavirus disease 2019 (COVID-19) threatens global public health and economy. In order to develop safe and effective vaccines, suitable animal models must be established. Here we report the rapid adaption of SARS-CoV-2 in BALB/c mice, based on which a convenient, economical and effective animal model was developed. Specifically, we found that mouse-adapted SARS-CoV-2 at passage 6 (MACSp6) efficiently infected both aged and young wild-type BALB/c mice, resulting in moderate pneumonia as well as inflammatory responses. The elevated infectivity of MACSp6 in mice could be attributed to the substitution of a key residue (N501Y) in the receptor-binding domain (RBD). Using this novel animal model, we further evaluated the in vivo protective efficacy of an RBD-based SARS-CoV-2 subunit vaccine, which elicited highly potent neutralizing antibodies and conferred full protection against SARS-CoV-2 MACSp6 challenge. This novel mouse model is convenient and effective in evaluating the in vivo protective efficacy of SARS-CoV-2 vaccine. ### Competing Interest Statement The authors have declared no competing interest.
2,716 downloads biochemistry
Zhenming Jin, Xiaoyu Du, Yechun Xu, Yongqiang Deng, Meiqin Liu, Yao Zhao, Bing Zhang, Xiaofeng Li, Leike Zhang, Chao Peng, Yinkai Duan, Jing Yu, Lin Wang, Kailin Yang, Fengjiang Liu, Rendi Jiang, Xinglou Yang, Tian You, Xiaoce Liu, Xiuna Yang, Fang Bai, Hong Liu, Xiang Liu, Luke W. Guddat, Wenqing Xu, Gengfu Xiao, Chengfeng Qin, Zhengli Shi, Hualiang Jiang, Zihe Rao, Haitao Yang
A new coronavirus (CoV) identified as COVID-19 virus is the etiological agent responsible for the 2019-2020 viral pneumonia outbreak that commenced in Wuhan–. Currently there is no targeted therapeutics and effective treatment options remain very limited. In order to rapidly discover lead compounds for clinical use, we initiated a program of combined structure-assisted drug design, virtual drug screening and high-throughput screening to identify new drug leads that target the COVID-19 virus main protease (Mpro). Mpro is a key CoV enzyme, which plays a pivotal role in mediating viral replication and transcription, making it an attractive drug target for this virus,. Here, we identified a mechanism-based inhibitor, N3, by computer-aided drug design and subsequently determined the crystal structure of COVID-19 virus Mpro in complex with this compound. Next, through a combination of structure-based virtual and high-throughput screening, we assayed over 10,000 compounds including approved drugs, drug candidates in clinical trials, and other pharmacologically active compounds as inhibitors of Mpro. Six of these inhibit Mpro with IC50 values ranging from 0.67 to 21.4 μM. Ebselen also exhibited promising antiviral activity in cell-based assays. Our results demonstrate the efficacy of this screening strategy, which can lead to the rapid discovery of drug leads with clinical potential in response to new infectious diseases where no specific drugs or vaccines are available. : #ref-1 : #ref-4 : #ref-5 : #ref-6
2,591 downloads immunology
Emanuele Andreano, Emanuele Nicastri, Ida Paciello, Piero Pileri, Noemi Manganaro, Giulia Piccini, Alessandro Manenti, Elisa Pantano, Anna Kabanova, Marco Troisi, Fabiola Vacca, Dario Cardamone, Concetta De Santi, Chiara Agrati, Maria Rosaria Capobianchi, Concetta Castilletti, Arianna Emiliozzi, Massimiliano Fabbiani, Francesca Montagnani, Emanuele Montomoli, Claudia Sala, Giuseppe Ippolito, Rino Rappuoli
In the absence of approved drugs or vaccines, there is a pressing need to develop tools for therapy and prevention of Covid-19. Human monoclonal antibodies have very good probability of being safe and effective tools for therapy and prevention of SARS-CoV-2 infection and disease. Here we describe the screening of PBMCs from seven people who survived Covid-19 infection to isolate human monoclonal antibodies against SARS-CoV-2. Over 1,100 memory B cells were single-cell sorted using the stabilized prefusion form of the spike protein and incubated for two weeks to allow natural production of antibodies. Supernatants from each cell were tested by ELISA for spike protein binding, and positive antibodies were further tested for neutralization of spike binding to receptor(s) on Vero E6 cells and for virus neutralization in vitro. From the 1,167 memory B specific for SARS-CoV-2, we recovered 318 B lymphocytes expressing human monoclonals recognizing the spike protein and 74 of these were able to inhibit the binding of the spike protein to the receptor. Finally, 17 mAbs were able to neutralize the virus when assessed for neutralization in vitro. Lead candidates to progress into the drug development pipeline will be selected from the panel of neutralizing antibodies identified with the procedure described in this study. ### Competing Interest Statement Dr. Rino Rappuoli is an employee of GSK group of companies.
2,577 downloads biophysics
The coronavirus SARS-CoV-2 uses an RNA-dependent RNA polymerase (RdRp) for the replication of its genome and the transcription of its genes. Here we present the cryo-electron microscopic structure of the SARS-CoV-2 RdRp in its replicating form. The structure comprises the viral proteins nsp12, nsp8, and nsp7, and over two turns of RNA template-product duplex. The active site cleft of nsp12 binds the first turn of RNA and mediates RdRp activity with conserved residues. Two copies of nsp8 bind to opposite sides of the cleft and position the RNA duplex as it exits. Long helical extensions in nsp8 protrude along exiting RNA, forming positively charged 'sliding poles' that may enable processive replication of the long coronavirus genome. Our results will allow for a detailed analysis of the inhibitory mechanisms used by antivirals such as remdesivir, which is currently in clinical trials for the treatment of coronavirus disease 2019 (COVID-19). ### Competing Interest Statement The authors have declared no competing interest.
2,554 downloads microbiology
Annika Kratzel, Daniel Todt, Philip V’kovski, Silvio Steiner, Mitra L Gultom, Tran Thi Nhu Thao, Nadine Ebert, Melle Holwerda, Jörg Steinmann, Daniela Niemeyer, Ronald Dijkman, Günter Kampf, Christian Drosten, Eike Steinmann, Volker Thiel, Stephanie Pfaender
The recent emergence of Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causing COVID-19 is a major burden for health care systems worldwide. It is important to address if the current infection control instructions based on active ingredients are sufficient. We therefore determined the virucidal activity of two alcohol-based hand rub solutions for hand disinfection recommended by the World Health Organization (WHO), as well as commercially available alcohols. Efficient SARS-CoV-2 inactivation was demonstrated for all tested alcohol-based disinfectants. These findings show the successful inactivation of SARS-CoV-2 for the first time and provide confidence in its use for the control of COVID-19.
2,513 downloads molecular biology
The emergence of a novel, highly pathogenic coronavirus, 2019-nCoV, in China, and its rapid national and international spread pose a global health emergency. Coronaviruses use their spike proteins to select and enter target cells and insights into nCoV-2019 spike (S)-driven entry might facilitate assessment of pandemic potential and reveal therapeutic targets. Here, we demonstrate that 2019-nCoV-S uses the SARS-coronavirus receptor, ACE2, for entry and the cellular protease TMPRSS2 for 2019-nCoV-S priming. A TMPRSS2 inhibitor blocked entry and might constitute a treatment option. Finally, we show that the serum from a convalescent SARS patient neutralized 2019-nCoV-S-driven entry. Our results reveal important commonalities between 2019-nCoV and SARS-coronavirus infection, which might translate into similar transmissibility and disease pathogenesis. Moreover, they identify a target for antiviral intervention.
2,507 downloads biochemistry
Xiangyang Chi, Renhong Yan, Jun Zhang, Guanying Zhang, Yuanyuan Zhang, Meng Hao, Zhe Zhang, Pengfei Fan, Yunzhu Dong, Yilong Yang, Zhengshan Chen, Yingying Guo, Jinlong Zhang, Yaning Li, Xiaohong Song, Yi Chen, Lu Xia, Ling Fu, Lihua Hou, Junjie Xu, Changming Yu, Jianmin Li, Qiang Zhou, Wei Chen
The pandemic of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) presents a global public health threat. Most research on therapeutics against SARS-CoV-2 focused on the receptor binding domain (RBD) of the Spike (S) protein, whereas the vulnerable epitopes and functional mechanism of non-RBD regions are poorly understood. Here we isolated and characterized monoclonal antibodies (mAbs) derived from convalescent COVID-19 patients. An mAb targeting the N-terminal domain (NTD) of the SARS-CoV-2 S protein, named 4A8, exhibits high neutralization potency against both authentic and pseudotyped SARS-CoV-2, although it does not block the interaction between angiotensin-converting enzyme 2 (ACE2) receptor and S protein. The cryo-EM structure of the SARS-CoV-2 S protein in complex with 4A8 has been determined to an overall resolution of 3.1 Angstrom and local resolution of 3.4 Angstrom for the 4A8-NTD interface, revealing detailed interactions between the NTD and 4A8. Our functional and structural characterizations discover a new vulnerable epitope of the S protein and identify promising neutralizing mAbs as potential clinical therapy for COVID-19. ### Competing Interest Statement The authors have declared no competing interest.
2,507 downloads microbiology
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. Next, we examined IFN competent Calu3 2B4 cells finding SARS-CoV-2 had reduced viral replication relative to SARS-CoV and induced STAT1 phosphorylation late during infection. 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. ### Competing Interest Statement
2,460 downloads immunology
Seth J Zost, Pavlo Gilchuk, Rita E. Chen, James Brett Case, Joseph X Reidy, Andrew Trivette, Rachel S Nargi, Rachel E Sutton, Naveenchandra Suryadevara, Elaine C Chen, Elad Binshtein, Swathi Shrihari, Mario Ostrowski, Helen Y. Chu, Jonathan E Didier, Keith W MacRenaris, Taylor Jones, Samuel Day, Luke Myers, F. Eun-Hyung Lee, Doan C Nguyen, Ignacio Sanz, David R. Martinez, Ralph S. Baric, Larissa B Thackray, Michael S. Diamond, Robert H. Carnahan, James E. Crowe
Antibodies are a principal determinant of immunity for most RNA viruses and have promise to reduce infection or disease during major epidemics. The novel coronavirus SARS-CoV-2 has caused a global pandemic with millions of infections and hundreds of thousands of deaths to date1,2. In response, we used a rapid antibody discovery platform to isolate hundreds of human monoclonal antibodies (mAbs) against the SARS-CoV-2 spike (S) protein. We stratify these mAbs into five major classes based on their reactivity to subdomains of S protein as well as their cross-reactivity to SARS-CoV. Many of these mAbs inhibit infection of authentic SARS-CoV-2 virus, with most neutralizing mAbs recognizing the receptor-binding domain (RBD) of S. This work defines sites of vulnerability on SARS-CoV-2 S and demonstrates the speed and robustness of existing antibody discovery methodologies ### Competing Interest Statement R.S.B. has served as a consultant for Takeda and Sanofi Pasteur on issues related to vaccines. M.S.D. is a consultant for Inbios Vir Biotechnology, NGM Biopharmaceuticals, Eli Lilly, and on the Scientific Advisory Board of Moderna, and a recipient of unrelated research grants from Moderna and Emergent BioSolutions. J.E.C. has served as a consultant for Sanofi and is on the Scientific Advisory Boards of CompuVax and Meissa Vaccines, is a recipient of previous unrelated research grants from Moderna and Sanofi and is Founder of IDBiologics, Inc. Vanderbilt University has applied for patents concerning SARS-CoV-2 antibodies that are related to this work. F.E.-H.L., D.C.N., and I.S. are inventors on a patent submitted for the plasmablast survival medium. J.D. and K.W.M. are employees of Berkeley Lights, Inc. All other authors declared no competing interests.
2,448 downloads microbiology
One of the greatest threats to humanity is the emergence of a pandemic virus. Among those with the greatest potential for such an event include influenza viruses and coronaviruses. In the last century alone, we have observed four major influenza A virus pandemics as well as the emergence of three highly pathogenic coronaviruses including SARS-CoV-2, the causative agent of the ongoing COVID-19 pandemic. As no effective antiviral treatments or vaccines are presently available against SARS-CoV-2, it is important to understand the host response to this virus as this may guide the efforts in development towards novel therapeutics. Here, we offer the first in-depth characterization of the host transcriptional response to SARS-CoV-2 and other respiratory infections through in vitro, ex vivo, and in vivo model systems. Our data demonstrate the each virus elicits both core antiviral components as well as unique transcriptional footprints. Compared to the response to influenza A virus and respiratory syncytial virus, SARS-CoV-2 elicits a muted response that lacks robust induction of a subset of cytokines including the Type I and Type III interferons as well as a numerous chemokines. Taken together, these data suggest that the unique transcriptional signature of this virus may be responsible for the development of COVID-19.
2,427 downloads genomics
COVID-19 has effectively spread worldwide. As of May 2020, Turkey is among the top ten countries with the most cases. A comprehensive genomic characterization of the virus isolates in Turkey is yet to be carried out. Here, we built a phylogenetic tree with 15,277 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) genomes. We identified the subtypes based on the phylogenetic clustering in comparison with the previously annotated classifications. We performed a phylogenetic analysis of the first thirty SARS-CoV-2 genomes isolated and sequenced in Turkey. Our results suggest that the first introduction of the virus to the country is earlier than the first reported case of infection. Virus genomes isolated from Turkey are dispersed among most types in the phylogenetic tree. Two of the seventeen sub-clusters were found enriched with the isolates of Turkey, which likely have spread expansively in the country. Finally, we traced virus genomes based on their phylogenetic placements. This analysis suggested multiple independent international introductions of the virus and revealed a hub for the inland transmission. We released a web application to track the global and interprovincial virus spread of the isolates from Turkey in comparison to thousands of genomes worldwide. ### Competing Interest Statement The authors have declared no competing interest.
2,400 downloads microbiology
Philip JM Brouwer, Tom G. Caniels, Karlijn van der Straten, Jonne L. Snitselaar, Yoann Aldon, Sandhya Bangaru, Jonathan L. Torres, Nisreen M.A. Okba, Mathieu Claireaux, Gius Kerster, Arthur E.H. Bentlage, Marlies M. van Haaren, Denise Guerra, Judith A. Burger, Edith E. Schermer, Kirsten D. Verheul, Niels van der Velde, Alex van der Kooi, Jelle van Schooten, Mariëlle J. van Breemen, Tom P. L. Bijl, Kwinten Sliepen, Aafke Aartse, Ronald Derking, Ilja Bontjer, Neeltje A. Kootstra, W. Joost Wiersinga, Gestur Vidarsson, Bart L. Haagmans, Andrew B. Ward, Godelieve J. de Bree, Rogier W. Sanders, Marit J. van Gils
The rapid spread of SARS-CoV-2 has a significant impact on global health, travel and economy. Therefore, preventative and therapeutic measures are urgently needed. Here, we isolated neutralizing antibodies from convalescent COVID-19 patients using a SARS-CoV-2 stabilized prefusion spike protein. Several of these antibodies were able to potently inhibit live SARS-CoV-2 infection at concentrations as low as 0.007 μg/mL, making them the most potent human SARS-CoV-2 antibodies described to date. Mapping studies revealed that the SARS-CoV-2 spike protein contained multiple distinct antigenic sites, including several receptor-binding domain (RBD) epitopes as well as previously undefined non-RBD epitopes. In addition to providing guidance for vaccine design, these mAbs are promising candidates for treatment and prevention of COVID-19. ### Competing Interest Statement Amsterdam UMC has filed a patent application on COVID-19 monoclonal antibodies.
2,394 downloads biochemistry
In December 2019, the first cases of a novel coronavirus infection causing COVID-19 were diagnosed in Wuhan, China. Viral Papain-Like cysteine protease (PLpro, NSP3) is essential for SARS-CoV-2 replication and represents a promising target for the development of antiviral drugs. Here, we used a combinatorial substrate library containing natural and a wide variety of nonproteinogenic amino acids and performed comprehensive activity profiling of SARS-CoV-2-PLpro. On the scaffold of best hits from positional scanning we designed optimal fluorogenic substrates and irreversible inhibitors with a high degree of selectivity for SARS PLpro variants versus other proteases. We determined crystal structures of two of these inhibitors (VIR250 and VIR251) in complex with SARS-CoV-2-PLpro which reveals their inhibitory mechanisms and provides a structural basis for the observed substrate specificity profiles. Lastly, we demonstrate that SARS-CoV-2-PLpro harbors deISGylating activities similar to SARS-CoV-1-PLpro but its ability to hydrolyze K48-linked Ub chains is diminished, which our sequence and structure analysis provides a basis for. Altogether this work has revealed the molecular rules governing PLpro substrate specificity and provides a framework for development of inhibitors with potential therapeutic value or drug repositioning. ### Competing Interest Statement F.E.O. declares competing financial interests as co-founders and shareholder of UbiQ Bio BV. M.B. is an employee and shareholder of Arvinas, Inc. The remaining authors declare no competing interests.
2,383 downloads neuroscience
David Brann, Tatsuya Tsukahara, Caleb Weinreb, Marcela Lipovsek, Koen Van den Berge, Boying Gong, Rebecca Chance, Iain C Macaulay, Hsin-jung Chou, Russell Fletcher, Diya Das, Kelly Street, Hector Roux de Bézieux, Yoon-Gi Choi, Davide Risso, Sandrine Dudoit, Elizabeth Purdom, Jonathan C Mill, Ralph Abi Hachem, Hiroaki Matsunami, Darren W. Logan, Bradley Goldstein, Matthew S Grubb, John Ngai, Sandeep Robert Datta
Altered olfactory function is a common symptom of COVID-19, but its etiology is unknown. A key question is whether SARS-CoV-2 (CoV-2) - the causal agent in COVID-19 - affects olfaction directly by infecting olfactory sensory neurons or their targets in the olfactory bulb, or indirectly, through perturbation of supporting cells. Here we identify cell types in the olfactory epithelium and olfactory bulb that express SARS-CoV-2 cell entry molecules. Bulk sequencing revealed that mouse, non-human primate and human olfactory mucosa expresses two key genes involved in CoV-2 entry, ACE2 and TMPRSS2. However, single cell sequencing and immunostaining demonstrated ACE2 expression in support cells, stem cells, and perivascular cells; in contrast, neurons in both the olfactory epithelium and bulb did not express ACE2 message or protein. These findings suggest that CoV-2 infection of non-neuronal cell types leads to anosmia and related disturbances in odor perception in COVID-19 patients. ### Competing Interest Statement DL is an employee of Mars, Inc. None of the other authors have competing interests to declare.
2,369 downloads microbiology
George Taiaroa, Daniel Rawlinson, Leo Featherstone, Miranda Pitt, Leon Caly, Julian Druce, Damian Purcell, Leigh Harty, Thomas Tran, Jason Roberts, Nichollas E. Scott, Mike Catton, Deborah Williamson, Lachlan Coin, Sebastian Duchene
Fundamental aspects of SARS-CoV-2 biology remain to be described, having the potential to provide insight to the response effort for this high-priority pathogen. Here we describe the first native RNA sequence of SARS-CoV-2, detailing the coronaviral transcriptome and epitranscriptome, and share these data publicly. A data-driven inference of viral genetic features and evolutionary rate is also made. The rapid sharing of sequence information throughout the SARS-CoV-2 pandemic represents an inflection point for public health and genomic epidemiology, providing early insights into the biology and evolution of this emerging pathogen.
2,351 downloads microbiology
Kenneth H. Dinnon, Sarah R. Leist, Alexandra Schäfer, Caitlin E. Edwards, David R. Martinez, Stephanie A. Montgomery, Ande West, Boyd L. Yount, Yixuan J. Hou, Lily E Adams, Kendra L Gully, Ariane J Brown, Emily Huang, Matthew D. Bryant, Ingrid C. Choong, Jeffrey S Glenn, Lisa E. Gralinski, Timothy P. Sheahan, Ralph S. Baric
Coronaviruses are prone to emergence into new host species most recently evidenced by SARS- CoV-2, the causative agent of the COVID-19 pandemic. Small animal models that recapitulate SARS-CoV-2 disease are desperately needed to rapidly evaluate medical countermeasures (MCMs). SARS-CoV-2 cannot infect wildtype laboratory mice due to inefficient interactions between the viral spike (S) protein and the murine ortholog of the human receptor, ACE2. We used reverse genetics to remodel the S and mACE2 binding interface resulting in a recombinant virus (SARS-CoV-2 MA) that could utilize mACE2 for entry. SARS-CoV-2 MA replicated in both the upper and lower airways of both young adult and aged BALB/c mice. Importantly, disease was more severe in aged mice, and showed more clinically relevant phenotypes than those seen in hACE2 transgenic mice. We then demonstrated the utility of this model through vaccine challenge studies in immune competent mice with native expression of mACE2. Lastly, we show that clinical candidate interferon (IFN) lambda-1a can potently inhibit SARS-CoV-2 replication in primary human airway epithelial cells in vitro, and both prophylactic and therapeutic administration diminished replication in mice. Our mouse-adapted SARS-CoV-2 model demonstrates age-related disease pathogenesis and supports the clinical use of IFN lambda-1a treatment in human COVID-19 infections. ### Competing Interest Statement M.D.B and I.C.C. are employees, and J.S.G is the founder and a board member, of Eiger BioPharmaceuticals, Inc., which produces peg-IFN-λ1.
2,309 downloads microbiology
Drug repositioning represents an effective way to control the current COVID-19 pandemic. Previously, we identified 24 FDA-approved drugs which exhibited substantial antiviral effect against SARS-CoV-2 in Vero cells. Since antiviral efficacy could be altered in different cell lines, we developed an antiviral screening assay with human lung cells, which is more appropriate than Vero cell. Comparative analysis of antiviral activities revealed that nafamostat is the most potent drug in human lung cells (IC50 = 0.0022μM). ### Competing Interest Statement The authors have declared no competing interest.
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