Dataset Information

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

ABSTRACT: Angiotensin-converting enzyme 2 (ACE2) and accessory proteases (TMPRSS2 and CTSL) are needed for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) cellular entry, and their expression may shed light on viral tropism and impact across the body. We assessed the cell-type-specific expression of ACE2, TMPRSS2 and CTSL across 107 single-cell RNA-sequencing studies from different tissues. ACE2, TMPRSS2 and CTSL are coexpressed in specific subsets of respiratory epithelial cells in the nasal passages, airways and alveoli, and in cells from other organs associated with coronavirus disease 2019 (COVID-19) transmission or pathology. We performed a meta-analysis of 31 lung single-cell RNA-sequencing studies with 1,320,896 cells from 377 nasal, airway and lung parenchyma samples from 228 individuals. This revealed cell-type-specific associations of age, sex and smoking with expression levels of ACE2, TMPRSS2 and CTSL. Expression of entry factors increased with age and in males, including in airway secretory cells and alveolar type 2 cells. Expression programs shared by ACE2⁺TMPRSS2⁺ cells in nasal, lung and gut tissues included genes that may mediate viral entry, key immune functions and epithelial-macrophage cross-talk, such as genes involved in the interleukin-6, interleukin-1, tumor necrosis factor and complement pathways. Cell-type-specific expression patterns may contribute to the pathogenesis of COVID-19, and our work highlights putative molecular pathways for therapeutic intervention.

SUBMITTER: Muus C

PROVIDER: S-EPMC9469728 | biostudies-literature | 2021 Mar

REPOSITORIES: biostudies-literature

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

Muus Christoph C Luecken Malte D MD Eraslan Gökcen G Sikkema Lisa L Waghray Avinash A Heimberg Graham G Kobayashi Yoshihiko Y Vaishnav Eeshit Dhaval ED Subramanian Ayshwarya A Smillie Christopher C Jagadeesh Karthik A KA Duong Elizabeth Thu ET Fiskin Evgenij E Torlai Triglia Elena E Ansari Meshal M Cai Peiwen P Lin Brian B Buchanan Justin J Chen Sijia S Shu Jian J Haber Adam L AL Chung Hattie H Montoro Daniel T DT Adams Taylor T Aliee Hananeh H Allon Samuel J SJ Andrusivova Zaneta Z Angelidis Ilias I Ashenberg Orr O Bassler Kevin K Bécavin Christophe C Benhar Inbal I Bergenstråhle Joseph J Bergenstråhle Ludvig L Bolt Liam L Braun Emelie E Bui Linh T LT Callori Steven S Chaffin Mark M Chichelnitskiy Evgeny E Chiou Joshua J Conlon Thomas M TM Cuoco Michael S MS Cuomo Anna S E ASE Deprez Marie M Duclos Grant G Fine Denise D Fischer David S DS Ghazanfar Shila S Gillich Astrid A Giotti Bruno B Gould Joshua J Guo Minzhe M Gutierrez Austin J AJ Habermann Arun C AC Harvey Tyler T He Peng P Hou Xiaomeng X Hu Lijuan L Hu Yan Y Jaiswal Alok A Ji Lu L Jiang Peiyong P Kapellos Theodoros S TS Kuo Christin S CS Larsson Ludvig L Leney-Greene Michael A MA Lim Kyungtae K Litviňuková Monika M Ludwig Leif S LS Lukassen Soeren S Luo Wendy W Maatz Henrike H Madissoon Elo E Mamanova Lira L Manakongtreecheep Kasidet K Leroy Sylvie S Mayr Christoph H CH Mbano Ian M IM McAdams Alexi M AM Nabhan Ahmad N AN Nyquist Sarah K SK Penland Lolita L Poirion Olivier B OB Poli Sergio S Qi CanCan C Queen Rachel R Reichart Daniel D Rosas Ivan I Schupp Jonas C JC Shea Conor V CV Shi Xingyi X Sinha Rahul R Sit Rene V RV Slowikowski Kamil K Slyper Michal M Smith Neal P NP Sountoulidis Alex A Strunz Maximilian M Sullivan Travis B TB Sun Dawei D Talavera-López Carlos C Tan Peng P Tantivit Jessica J Travaglini Kyle J KJ Tucker Nathan R NR Vernon Katherine A KA Wadsworth Marc H MH Waldman Julia J Wang Xiuting X Xu Ke K Yan Wenjun W Zhao William W Ziegler Carly G K CGK

Nature medicine 20210302 3

Angiotensin-converting enzyme 2 (ACE2) and accessory proteases (TMPRSS2 and CTSL) are needed for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) cellular entry, and their expression may shed light on viral tropism and impact across the body. We assessed the cell-type-specific expression of ACE2, TMPRSS2 and CTSL across 107 single-cell RNA-sequencing studies from different tissues. ACE2, TMPRSS2 and CTSL are coexpressed in specific subsets of respiratory epithelial cells in the nasal ...[more]

PMID: 33654293

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Project description:Single-cell RNA-seq has been used to characterize human COVID-19. To determine if preclinical models successfully mimic the cell-intrinsic and -extrinsic effects of severe disease, we conducted a meta-analysis of single-cell data across five model species. To assess whether dissemination of viral RNA in lung cells tracks pathology and results in cell-intrinsic and -extrinsic transcriptomic changes in COVID-19. We conducted a meta-analysis by analyzing six publicly available, scRNA-seq data sets. We used dual mapping (host and virus) and differential gene expression analyses to compare viral+ and viral- cell populations. We conducted a principal component analysis to identify successful models of human COVID-19. We found expression of viral RNA in many non-epithelial cell types. Fibroblasts, macrophages, and endothelial cells exhibit clear evidence of viral-intrinsic and -extrinsic effects on host gene expression. Using viral RNA expression, we found that K18-hACE2 mice most closely modeled severe human COVID-19, followed by hamsters. Ferrets and macaques are poor models of human disease due to the low presence of viral RNA. Moreover, we found that increased transcripts of certain key inflammatory genes such as IL1B, IL18, and CXCL10 are not restricted to virally infected cells, suggesting these genes are regulated in a paracrine or autocrine fashion. These data affirm widespread dissemination of viral RNA in the lung, which may be key in the pathogenesis of severe COVID-19 and demonstrate ferrets and Rhesus macaques are poor models of human COVID-19. IMPORTANCE We conducted a high-resolution meta-analysis of scRNA-seq data from humans and five animal models of COVID-19. This study reports viral RNA dissemination in several cell types in human data as well as in some of the pre-clinical models. Using this metric, the K18-hACE2 mouse model, followed by the hamster model, most closely resembled human COVID-19. We observed clear evidence of viral-intrinsic effects within cells (e.g., IRF5 expression) as well as viral-extrinsic cytokine modulation (e.g., IL1B, IL18, CXCL10). We observed proinflammatory chemokine expression in cells devoid of viral RNA expression, suggesting autocrine/paracrine interferon regulation. This report serves as a resource-synthesizing data from COVID-19 humans and animal models and suggesting improvements for relevant pre-clinical models that may aid future diagnostic and therapeutic development projects.

Dataset Information

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

Publications

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

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