Journal Article

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

Vaishnav, Eeshit Dhaval, Montoro, Daniel T., Smillie, Christopher, Deprez, Marie, Nabhan, Ahmad N., Slyper, Michal, Qi, CanCan, McAdams, Alexi M., Ghazanfar, Shila, Chung, Hattie, Lukassen, Soeren, Duong, Elizabeth Thu, Shea, Conor V., Travaglini, Kyle J., Sun, Dawei, Chiou, Joshua, Larsson, Ludvig, Penland, Lolita, Bolt, Liam, Vernon, Katherine A., Schupp, Jonas C., Chichelnitskiy, Evgeny, Heimberg, Graham, Xu, Ke, Gould, Joshua, Wang, Xiuting, Cuoco, Michael S., Benhar, Inbal, Bergenstråhle, Ludvig, Queen, Rachel, Sikkema, Lisa, Shu, Jian, Leroy, Sylvie, Poli, Sergio, Sullivan, Travis B., Ansari, Meshal, Chen, Sijia, Cuomo, Anna S. E., Mayr, Christoph H., Gutierrez, Austin J., Bécavin, Christophe, Tucker, Nathan R., Wadsworth, Marc H., Braun, Emelie, Hu, Lijuan, Bui, Linh T., Ashenberg, Orr, Fischer, David S., Bassler, Kevin, Tan, Peng, Cai, Peiwen, He, Peng, Ludwig, Leif S., Kapellos, Theodoros S., Sinha, Rahul, Callori, Steven, Zhao, William, Duclos, Grant, Andrusivova, Zaneta, Rosas, Ivan, Talavera-López, Carlos, Torlai Triglia, Elena, Fine, Denise, Shi, Xingyi, Yan, Wenjun, Eraslan, Gökcen, Mamanova, Lira, Koba

2021

Overview

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. An integrated analysis of over 100 single-cell and single-nucleus transcriptomics studies illustrates severe acute respiratory syndrome coronavirus 2 viral entry gene coexpression patterns across different human tissues, and shows association of age, smoking status and sex with viral entry gene expression in respiratory cell populations.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 631/114 / 631/250 / 631/326/596/4130 / 631/337/2019 / 692/699/255/2514 / ACE2 / Adult / Age / Aged / Aged, 80 and over / Alveolar Epithelial Cells - metabolism / Alveolar Epithelial Cells - virology / Alveoli / Analysis / Angiotensin / Angiotensin-converting enzyme 2 / Angiotensin-Converting Enzyme 2 - genetics / Angiotensin-Converting Enzyme 2 - metabolism / Biomedical and Life Sciences / Biomedicine / Cancer Research / Cathepsin L - genetics / Cathepsin L - metabolism / Coronaviridae / Coronaviruses / COVID-19 / COVID-19 - epidemiology / COVID-19 - genetics / COVID-19 - pathology / COVID-19 - virology / Crosstalk / Cytokines / Datasets as Topic - statistics & numerical data / Demographic aspects / Demographics / Demography / Disease transmission / Epidemics / Epithelial cells / Female / Gene expression / Gene Expression Profiling - statistics & numerical data / Gene sequencing / Genes / Genetic aspects / Host-Pathogen Interactions - genetics / Human tissues / Humans / Infectious Diseases / Interleukin 1 / Interleukin 6 / Lung - metabolism / Lung - virology / Lungs / Macrophages / Male / Meta-analysis / Metabolic Diseases / Middle Aged / Molecular Medicine / Neurosciences / Organ Specificity - genetics / Organs / Parenchyma / Pathogenesis / Peptidyl-dipeptidase A / Quorum sensing / Respiration / Respiratory diseases / Respiratory System - metabolism / Respiratory System - virology / Respiratory tract / Ribonucleic acid / RNA / SARS-CoV-2 - physiology / Sequence Analysis, RNA - methods / Sequence Analysis, RNA - statistics & numerical data / Serine Endopeptidases - genetics / Serine Endopeptidases - metabolism / Severe acute respiratory syndrome coronavirus 2 / Sex / Single-Cell Analysis - methods / Single-Cell Analysis - statistics & numerical data / Smoking / Transcriptomics / Tropism / United States / Viral diseases / Virus Internalization