TY - JOUR
T1 - Single-cell meta-analysis of SARS-CoV-2 entry genes across tissues and demographics
AU - NHLBI LungMap Consortium
AU - Human Cell Atlas Lung Biological Network
AU - Muus, Christoph
AU - Luecken, Malte D
AU - Eraslan, Gökcen
AU - Sikkema, Lisa
AU - Waghray, Avinash
AU - Heimberg, Graham
AU - Kobayashi, Yoshihiko
AU - Vaishnav, Eeshit Dhaval
AU - Subramanian, Ayshwarya
AU - Smillie, Christopher
AU - Jagadeesh, Karthik A
AU - Duong, Elizabeth Thu
AU - Fiskin, Evgenij
AU - Triglia, Elena Torlai
AU - Ansari, Meshal
AU - Cai, Peiwen
AU - Lin, Brian
AU - Buchanan, Justin
AU - Chen, Sijia
AU - Shu, Jian
AU - Haber, Adam L
AU - Chung, Hattie
AU - Montoro, Daniel T
AU - Adams, Taylor
AU - Aliee, Hananeh
AU - Allon, Samuel J
AU - Andrusivova, Zaneta
AU - Angelidis, Ilias
AU - Ashenberg, Orr
AU - Bassler, Kevin
AU - Bécavin, Christophe
AU - Benhar, Inbal
AU - Bergenstråhle, Joseph
AU - Bergenstråhle, Ludvig
AU - Bolt, Liam
AU - Braun, Emelie
AU - Bui, Linh T
AU - Callori, Steven
AU - Chaffin, Mark
AU - Chichelnitskiy, Evgeny
AU - Chiou, Joshua
AU - Conlon, Thomas M
AU - Cuoco, Michael S
AU - Cuomo, Anna S E
AU - Deprez, Marie
AU - Duclos, Grant
AU - Fine, Denise
AU - Fischer, David S
AU - Hu, Yan
AU - Qi, CanCan
AU - Nawijn, Martijn
PY - 2021/3
Y1 - 2021/3
N2 - 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.
AB - 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.
KW - Adult
KW - Aged
KW - Aged, 80 and over
KW - Alveolar Epithelial Cells/metabolism
KW - Angiotensin-Converting Enzyme 2/genetics
KW - COVID-19/epidemiology
KW - Cathepsin L/genetics
KW - Datasets as Topic/statistics & numerical data
KW - Demography
KW - Female
KW - Gene Expression Profiling/statistics & numerical data
KW - Host-Pathogen Interactions/genetics
KW - Humans
KW - Lung/metabolism
KW - Male
KW - Middle Aged
KW - Organ Specificity/genetics
KW - Respiratory System/metabolism
KW - SARS-CoV-2/physiology
KW - Sequence Analysis, RNA/methods
KW - Serine Endopeptidases/genetics
KW - Single-Cell Analysis/methods
KW - Virus Internalization
U2 - 10.1038/s41591-020-01227-z
DO - 10.1038/s41591-020-01227-z
M3 - Article
C2 - 33654293
SN - 1078-8956
VL - 27
SP - 546
EP - 559
JO - Nature Medicine
JF - Nature Medicine
IS - 3
ER -