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

The expression of ACE2 and TMPRSS2 in lung, nasal and gut epithelial cells is associated with expression programs with many shared features, involving key immunological genes and genes related to viral infection, raising many hypotheses for future studies, especially as more patient tissue samples are analyzed in the coming months. In the lung, epithelial cells express IL6, IL6R and IL6ST, which raises the hypothesis that infection may trigger cytokine expression from these cells and contribute to uncontrolled immunological responses. The immune-like programs in these cells are further reinforced by the accessibility of STAT and IRF binding sites in scATAC-Seq data, consistent with another study from our network showing the role of interferon in regulating ACE2 expression in epithelial cells 46 . Notably, scRNA-Seq analysis of immune cells from bronchoalveolar lavage fluid of COVID-19 patients identified high activity of transcription factors such as STAT1/2 and IRF1/2/5/7/8/9 in macrophage states increased in severe COVID-19 patients 151 . Other hypotheses for future studies include lysosomal genes in dual positive lung secretory and multiciliated cells, which may be consistent with putative "viral entry" cells, and RIPK3 expression in the cell programs of airway cells, which opens the hypothesis of necroptosis initiating a pro-inflammatory response. Interestingly, we observed relatively high enrichment of ACE2 in secretory cell types (mucous cells and AT2 cells). We speculate that viruses may take advantage of the rich secretory pathway components in these cells for their efficient dispersal. Additionally, SMGs of the airways are recently shown to serve as reservoirs of reserve stem cells 152, 153 . Therefore, we also speculate that SMGs similarly may serve as reservoirs for viruses where they can escape from muco-ciliary transport and mechanical expulsion associated with severe cough in the airway luminal surface.