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

One intriguing clinical observation is that some COVID-19 patients display an array of neurologic symptoms 116, 117, 118 , reported as seizures and acute necrotizing encephalopathy, similar to that previously observed following other infections such as influenza 119, 120 . Neuroinflammation could result from direct viral infection of the brain, or a systemic cytokine storm 121-123,124-126,121-123 . Direct viral invasion of SARS-CoV and MERS-CoV is observed in multiple brain regions in human patients and mouse models 124, 125 , consistent with widespread ACE2 expression in numerous brain cell types. Furthermore, SARS-CoV has been shown to infiltrate the brain via the olfactory epithelium-olfactory bulb axis 127 ; olfactory transmission for SARS-CoV-2 has been recently proposed 128 . Other possible transmission routes could be through the infection of ACE2 + TMPRSS2 + enteric neurons synapsing with vagal afferents, or entry through blood-CNS interfaces such as the choroid plexus or meninges 121,129-131 . Profiling immune cells at these sites after infection is an important future step to better understand how the viral response may lead to encephalitis. One intriguing possibility is that encephalitis might arise as an autoimmune response to myelin antigens expressed by infected cells. Antibodies against peptides of myelin proteins have been clinically shown to be associated with autoimmune encephalitis and seizures [132] [133] [134] , and myelin peptides are targets of T cells 135 in demyelinating inflammatory neurological diseases such as acute demyelinating encephalomyelitis, Guillain-Barre Syndrome, and multiple sclerosis [135] [136] [137] [138] [139] [140] [141] [142] . Oligodendrocytes, the myelin-producing cells of the CNS, are the main ACE2 + TMPRSS2 + cell type in the brain, the myelin transcriptional regulator MYRF was enriched in certain ACE2 + TMPRSS2 + cell types as noted above, and myelin proteins MOG and MBP were coexpressed in numerous ACE2+ clusters across organs. MYRF and MBP were significantly differentially expressed in ACE2 + TMPRSS2 + subsets of the lung and gut (Supplementary Table 10 ); myelin targeting Th17 cells trained in the gut are able to infiltrate the CNS in a mouse model of experimental autoimmune encephalomyelitis 143 . Taken together, the expression of myelin proteins across multiple ACE2 + TMPRSS2 + cells may hypothetically contribute to antigen presentation and autoimmune response in the context of viral infection. A small number of COVID-19 patients were reported to have Guillain-Barre Syndrome 144 , with a demyelinating process in some; this is consistent with observations of Guillain-Barre Syndrome following other viral infections such as Zika, influenza, and Epstein-Barr virus 139, 145, 146 . Whether anti myelin specific immunity can be induced by virus infected cells expressing myelin proteins remains an area for future study.