Integrated analyses of single-cell atlases reveal age, gender, and smoking status associations with cell type-specific expression of mediators of SARS-CoV-2 viral entry and highlights inflammatory programs in putative target cells

Christoph Muus; Malte D Luecken; Gokcen Eraslan; Avinash Waghray; Graham Heimberg; Lisa Sikkema; Yoshihiko Kobayashi; Eeshit Dhaval Vaishnav; Ayshwarya Subramanian; Christopher Smillie; Karthik Jagadeesh; Elizabeth Thu Duong; Evgenij Fiskin; Elena Torlai Triglia; Christophe Becavin; Meshal Ansari; Peiwen Cai; Brian Lin; Justin Buchanan; Sijia Chen; Jian Shu; Adam L Haber; Hattie Chung; Daniel T Montoro; Taylor Adams; Hananeh Aliee; Samuel J Allon; Zaneta Andrusivova; Ilias Angelidis; Orr Ashenberg; Kevin Bassler; Christophe Becavin; Inbal Benhar; Joseph Bergenstrahle; Ludvig Bergenstrahle; Liam Bolt; Emelie Braun; Linh T Bui; Mark Chaffin; Evgeny Chichelnitskiy; Joshua Chiou; Thomas M Conlon; Michael S Cuoco; Marie Deprez; David S Fischer; Astrid Gillich; Joshua Gould; Minzhe Guo; Austin J Gutierrez; Arun C Habermann; Tyler Harvey; Peng He; Xiaomeng Hou; Lijuan Hu; Alok Jaiswal; Peiyong Jiang; Theodoros Kapellos; Christin S Kuo; Ludvig Larsson; Michael A Leney-Greene; Kyungtae Lim; Monika Litvinukova; Ji Lu; Leif S Ludwig; Wendy Luo; Henrike Maatz; Elo Maddissoon; Lira Mamanova; Kasidet Manakongtreecheep; Charles-Hugo Marquette; Ian Mbano; Alexi M McAdams; Ross J Metzger; Ahmad N Nabhan; Sarah K Nyquist; Jose Ordovas-Montanes; Lolita Penland; Olivier B Poirion; Segio Poli; CanCan Qi; Daniel Reichart; Ivan Rosas; Jonas Schupp; Rahul Sinha; Rene V Sit; Kamil Slowikowski; Michal Slyper; Neal Smith; Alex Sountoulidis; Maximilian Strunz; Dawei Sun; Carlos Talavera-Lopez; Peng Tan; Jessica Tantivit; Kyle J Travaglini; Nathan R Tucker; Katherine Vernon; Marc H Wadsworth; Julia Waldman; Xiuting Wang; Wenjun Yan; Ali Onder Yildirim; William Zhao; Carly G K Ziegler; Aviv Regev

TMPRSS2 has been demonstrated to mediate SARS-CoV-2 infection in vitro 37, 44 , but SARS-CoV-2 also infects cells in the absence of TMPRSS2 37 . Thus, additional proteases likely play roles in proteolytic cleavage events of spike and other viral proteins that underlie entry (fusion) and egress. To systematically predict proteases potentially involved in SARS-CoV-2 pathogenesis, we tested for co-expression of each of 625 annotated human protease genes 102 with ACE2 in the large declined donor transplant dataset ("Regev/Rajagopal") from 10 patients. The analysis recovered TMPRSS2 as one of the significantly co-expressed in multiple lung epithelial cell types (Fig. 6a , Supplementary Table 11, 12 ). In addition, multiple members of the proprotein convertase subtilisin kexin (PCSK) family were also significantly co-expressed with ACE2 in both proximal and distal airway epithelial cells (Fig. 6a,b) , including FURIN, PCSK2, PCSK5, PCSK6 and PCSK7 in AT2 cells. Proprotein convertases have known roles in coronavirus S-protein priming 43, 103, 104 . We obtained similar results in an independent dataset of 182,952 cells from 40 donors (Extended Data Fig. 14a ,b, "aggregated lung").