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

Cell programs from multiple tissues (Fig. 4c,d) included genes related to TNF signaling (e.g., BIRC3, CCL20, CXCL1, CXCL2, JUN, NFKB1), raising the possibility that anti-TNF therapy may impact the expression of ACE2 and/or TMPRSS2. Consistent with this hypothesis, ACE2 expression in enterocytes was significantly lower in ulcerative colitis patients treated with anti-TNF compared to untreated patients (mean = 0.22 and 0.13 log2(transcripts per 10,000 (TP10K)+1) in treated vs. untreated; adjusted P < 1e-3). However, we could not control for many important features, including disease severity, which is strongly associated with anti-TNF treatment, raising the need for future work. Some of the genes are targets of known drugs 88 . For example, dualpositive lung secretory cells expressed, in addition to ACE2 (targeted by ACE inhibitors), other drug targets, including C3, HDAC9, IL23A, PIK3CA, RAMP1, and SLC7A11. Other program genes were shown to interact with SARS-CoV-2 proteins via affinity purification mass spectrometry 89 . Among those was GDF15, which was identified as a putative interaction partner for the SARS-CoV-2 protein Orf8 89 , is a central regulator of inflammation 90 , and was a member of the dual-positive cell programs of both lung basal cells and nasal multiciliated cells.