RAPID: Single-cell dissection of the cell types and mechanisms underlying SARS-CoV-2 entry in host cells via the ACE2 receptor and protease TMPRSS2

RAPID：单细胞解剖 SARS-CoV-2 通过 ACE2 受体和蛋白酶 TMPRSS2 进入宿主细胞的细胞类型和机制

• 批准号: 2028295
• 负责人: Alexander Tsankov
• 金额: $ 20万
• 依托单位: Icahn School of Medicine at Mount Sinai
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-01 至 2021-05-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2028295&HistoricalAwards=false
• 关键词: RAPID; Single; cell; dissection; types

The new coronavirus (SARS-CoV-2) is a global threat to worldwide economies and public health due to its highly contagious nature and rapid spread. To develop optimal strategies for containment and treatment of the coronavirus epidemic, it is critical to understand the cell types and biological mechanisms that mediate viral entry and propagation across the human population. Recent advancements in single-cell technologies now make it possible to measure the expression of genes at a cell-type resolution. This project aims to provide a comprehensive survey of the cell types used by SARS-CoV-2 for viral entry across the nasal airways, lung, and gut tissue and to understand physiological basis of how age, gender, and smoking history may predispose healthy individuals to infection. Identification of cells containing the two proteins known to mediate viral entry [the receptor protein angiotensin-converting enzyme-2 (ACE2) and the transmembrane serine protease 2 (TMPRSS2)] will elucidate the gene expression programs and signaling pathways associated with cells used by the novel coronavirus for host entry. Analysis of single-cell chromatin accessibility (scATAC-seq) data from the lung will identify the cell-type specific transcription factors and regulatory regions associated with these gene expression programs. This improved understanding of the signaling pathways, gene expression programs, and regulatory mechanisms of coronavirus infection of cells may lead to novel, patient- and region-specific therapeutic targets to combat the spread of SARS-CoV-2. The single-cell data will be made available for download, analysis, and visualization, thus providing a valuable resource to the scientific community.In addition to dissemination of the findings and contributing to potential treatment strategies for the control of coronavirus infection, the project will support the training and professional development of a data scientist and of a computational research associate.The catastrophic effects of the COVID-19 pandemic caused by the novel coronavirus (SARS-CoV-2) highlights an urgent need for improving scientific understanding of the underlying mechanisms of viral entry and propagation. SARS-CoV-2 uses the host ACE2 receptor protein and protease TMPRSS2 to gain cellular entry; however, what organs and cell types express these genes and how they interact with the host immune system remain obscure. Recent advancements in single-cell technologies now allow for the dissection of cell types and cell states at unprecedented resolution, which has led to groundbreaking discoveries in tissue biology. This project will integrate single-cell RNA-sequencing data across multiple individuals to assess how expression patterns of ACE2 and TMPRSS2 in the lung, the primary organ linked to coronavirus infection, are associated with an individual’s age, gender and smoking history. It will also provide a broader context of the distinct cell types in the lung and gut expressing ACE2 and TMPRSS2 and elucidate the gene expression programs and signaling pathways that are associated with viral entry in healthy individuals. Finally, analysis of single-cell chromatin accessibility data from different lung regions will identify the key transcription factors and regulatory mechanisms driving the expression programs related to viral entry. Taken together, this project will lead to a better understanding of coronavirus infection mechanisms. This RAPID award is made by the Physiological Mechanisms and Biomechanics Program and the Symbiosis, Defense, and Self-recognition Program in the BIO Division of Integrative Organismal Systems, using funds from the Coronavirus Aid, Relief, and Economic Security (CARES) Act.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

新型冠状病毒（SARS-CoV-2）由于其高度传染性和快速传播，对全球经济和公共卫生构成全球威胁。为了制定遏制和治疗冠状病毒流行病的最佳策略，了解介导病毒进入和在人群中传播的细胞类型和生物学机制至关重要。单细胞技术的最新进展现在使得以细胞类型分辨率测量基因表达成为可能。该项目旨在提供SARS-CoV-2用于病毒进入鼻气道，肺和肠道组织的细胞类型的全面调查，并了解年龄，性别和吸烟史如何使健康个体易于感染的生理基础。鉴定含有已知介导病毒进入的两种蛋白质[受体蛋白血管紧张素转换酶-2（ACE 2）和跨膜丝氨酸蛋白酶2（TMPRSS 2）]的细胞将阐明与新型冠状病毒用于宿主进入的细胞相关的基因表达程序和信号通路。来自肺的单细胞染色质可及性（scATAC-seq）数据的分析将鉴定与这些基因表达程序相关的细胞类型特异性转录因子和调控区域。这种对细胞冠状病毒感染的信号通路、基因表达程序和调控机制的理解的提高可能会导致新的、患者和区域特异性的治疗靶点，以对抗SARS-CoV-2的传播。单细胞数据将可供下载、分析和可视化，从而为科学界提供宝贵的资源。除了传播研究结果和为控制冠状病毒感染的潜在治疗策略做出贡献外，该项目将支持数据科学家和计算研究助理的培训和专业发展。COVID-19的灾难性影响新型冠状病毒（SARS-CoV-2）引起的19大流行凸显了迫切需要提高对病毒进入和传播的潜在机制的科学理解。SARS-CoV-2利用宿主ACE 2受体蛋白和蛋白酶TMPRSS 2进入细胞;然而，什么器官和细胞类型表达这些基因以及它们如何与宿主免疫系统相互作用仍然不清楚。单细胞技术的最新进展现在允许以前所未有的分辨率解剖细胞类型和细胞状态，这导致了组织生物学的突破性发现。该项目将整合多个个体的单细胞RNA测序数据，以评估与冠状病毒感染相关的主要器官肺中ACE 2和TMPRSS 2的表达模式如何与个体的年龄，性别和吸烟史相关。它还将提供肺和肠中表达ACE 2和TMPRSS 2的不同细胞类型的更广泛背景，并阐明与健康个体中病毒进入相关的基因表达程序和信号通路。最后，分析来自不同肺区域的单细胞染色质可及性数据将确定驱动与病毒进入相关的表达程序的关键转录因子和调控机制。总之，该项目将有助于更好地了解冠状病毒感染机制。该RAPID奖项由生理机制和生物力学计划以及生物综合系统部的共生，防御和自我认可计划颁发，使用冠状病毒援助，救济和经济安全（CARES）法案的资金。该奖项反映了NSF的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

项目成果

Single-cell meta-analysis of SARS-CoV-2 entry genes across tissues and demographics.

• DOI: 10.1038/s41591-020-01227-z
• 发表时间: 2021-03
• 期刊: NATURE MEDICINE
• 影响因子: 82.9
• 作者: Muus, Christoph;Luecken, Malte D.;Eraslan, Gokcen;Sikkema, Lisa;Waghray, Avinash;Heimberg, Graham;Kobayashi, Yoshihiko;Vaishnav, Eeshit Dhaval;Subramanian, Ayshwarya;Smillie, Christopher;Jagadeesh, Karthik A.;Duong, Elizabeth Thu;Fiskin, Evgenij;Triglia, Elena Torlai;Ansari, Meshal;Cai, Peiwen;Lin, Brian;Buchanan, Justin;Chen, Sijia;Shu, Jian;Haber, Adam L.;Chung, Hattie;Montoro, Daniel T.;Adams, Taylor;Aliee, Hananeh;Allon, Samuel J.;Andrusivova, Zaneta;Angelidis, Ilias;Ashenberg, Orr;Bassler, Kevin;Becavin, Christophe;Benhar, Inbal;Bergenstrahle, Joseph;Bergenstrahle, Ludvig;Bolt, Liam;Braun, Emelie;Bui, Linh T.;Callori, Steven;Chaffin, Mark;Chichelnitskiy, Evgeny;Chiou, Joshua;Conlon, Thomas M.;Cuoco, Michael S.;Cuomo, Anna S. E.;Deprez, Marie;Duclos, Grant;Fine, Denise;Fischer, David S.;Ghazanfar, Shila;Gillich, Astrid;Giotti, Bruno;Gould, Joshua;Guo, Minzhe;Gutierrez, Austin J.;Habermann, Arun C.;Harvey, Tyler;He, Peng;Hou, Xiaomeng;Hu, Lijuan;Hu, Yan;Jaiswal, Alok;Ji, Lu;Jiang, Peiyong;Kapellos, Theodoros S.;Kuo, Christin S.;Larsson, Ludvig;Leney-Greene, Michael A.;Lim, Kyungtae;Litvinukova, Monika;Ludwig, Leif S.;Lukassen, Soeren;Luo, Wendy;Maatz, Henrike;Madissoon, Elo;Mamanova, Lira;Manakongtreecheep, Kasidet;Leroy, Sylvie;Mayr, Christoph H.;Mbano, Ian M.;McAdams, Alexi M.;Nabhan, Ahmad N.;Nyquist, Sarah K.;Penland, Lolita;Poirion, Olivier B.;Poli, Sergio;Qi, CanCan;Queen, Rachel;Reichart, Daniel;Rosas, Ivan;Schupp, Jonas C.;Shea, Conor, V;Shi, Xingyi;Sinha, Rahul;Sit, Rene, V;Slowikowski, Kamil;Slyper, Michal;Smith, Neal P.;Sountoulidis, Alex;Strunz, Maximilian;Sullivan, Travis B.;Sun, Dawei;Talavera-Lopez, Carlos;Tan, Peng;Tantivit, Jessica;Travaglini, Kyle J.;Tucker, Nathan R.;Vernon, Katherine A.;Wadsworth, Marc H.;Waldman, Julia;Wang, Xiuting;Xu, Ke;Yan, Wenjun;Zhao, William;Ziegler, Carly G. K.
• 通讯作者: Ziegler, Carly G. K.

Longitudinal Multi-omics Analyses Identify Responses of Megakaryocytes, Erythroid Cells, and Plasmablasts as Hallmarks of Severe COVID-19.

• DOI: 10.1016/j.immuni.2020.11.017
• 发表时间: 2020-12-15
• 期刊: Immunity
• 影响因子: 32.4
• 作者: Bernardes JP;Mishra N;Tran F;Bahmer T;Best L;Blase JI;Bordoni D;Franzenburg J;Geisen U;Josephs-Spaulding J;Köhler P;Künstner A;Rosati E;Aschenbrenner AC;Bacher P;Baran N;Boysen T;Brandt B;Bruse N;Dörr J;Dräger A;Elke G;Ellinghaus D;Fischer J;Forster M;Franke A;Franzenburg S;Frey N;Friedrichs A;Fuß J;Glück A;Hamm J;Hinrichsen F;Hoeppner MP;Imm S;Junker R;Kaiser S;Kan YH;Knoll R;Lange C;Laue G;Lier C;Lindner M;Marinos G;Markewitz R;Nattermann J;Noth R;Pickkers P;Rabe KF;Renz A;Röcken C;Rupp J;Schaffarzyk A;Scheffold A;Schulte-Schrepping J;Schunk D;Skowasch D;Ulas T;Wandinger KP;Wittig M;Zimmermann J;Busch H;Hoyer BF;Kaleta C;Heyckendorf J;Kox M;Rybniker J;Schreiber S;Schultze JL;Rosenstiel P;HCA Lung Biological Network;Deutsche COVID-19 Omics Initiative (DeCOI)
• 通讯作者: Deutsche COVID-19 Omics Initiative (DeCOI)

SARS-CoV-2 Receptor ACE2 Is an Interferon-Stimulated Gene in Human Airway Epithelial Cells and Is Detected in Specific Cell Subsets across Tissues

• DOI: 10.1016/j.cell.2020.04.035
• 发表时间: 2020-05-28
• 期刊: CELL
• 影响因子: 64.5
• 作者: Ziegler, Carly G. K.;Allon, Samuel J.;Ordovas-Montanes, Jose
• 通讯作者: Ordovas-Montanes, Jose