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

We focused on trends or indications in those cell types where both TMPRSS2 and ACE2 are predominantly expressed in the lung: airway epithelial cells (basal, multiciliated, and secretory cells), alveolar AT2 cells, and submucosal gland secretory cells (Fig. 3e) . Strikingly, we find robust trends of ACE2 expression with age, sex, and smoking status in these cell types (Fig. 3d , Extended Data Fig. 6 and MALTE4): ACE2 expression increases with age in basal and multiciliated cells. ACE2 expression is elevated in males in airway secretory cells and alveolar AT2 cells. Furthermore, we find strongly elevated levels of ACE2 in past or current smokers in multiciliated cells (log fold change (log FC): 1.52, Fig. 3d ). Significant associations of ACE2 expression indicate increased expression with age in AT2 (largest age effect: slope of log expression per year of 0.020) and secretory cells, and increased expression of ACE2 in males in multiciliated cells. Further indications associate past or current smoking with decreased ACE2 expression in AT2 cells, and increased ACE2 expression in basal cells. However, these last five indications are not robust trends and depend on the inclusion of a single dataset (Fig. 3f) , often because that dataset contributes a large number of cells of a particular type. Specifically, when we held out the largest declined donor transplant dataset (Supplementary Table 2 , "Regev-Rajagopal", most cells and most samples), a declined donor tracheal epithelium dataset ("Seibold", Supplementary Table 2 , most donors in the smoking analysis), or a further declined donor lung dataset ("Kropski-Banovich", Supplementary Table 2 ) respectively, the effect is no longer present (Methods, Fig. 3f , Supplemenatry Data D1).