SARS-CoV-2 Receptor ACE2 is an Interferon-Stimulated Gene in Human Airway Epithelial Cells and Is Enriched in Specific Cell Subsets Across Tissues

Ziegler, Carly G.K.; Allon, Samuel J.; Nyquist, Sarah K.; Mbano, Ian M.; Miao, Vincent N.; Cao, Yuming; Yousif, Ashraf S.; Bals, Julia; Hauser, Blake M.; Feldman, Jared; Muus, Christoph; Wadsworth, Marc H.; Kazer, Samuel W.; Hughes, Travis; Doran, Benjamin; Gatter, G. James; Vukovic, Marko; Tzouanas, Constantine N.; Taliaferro, Faith; Guo, Zhiru; Wang, Jennifer; Dwyer, Daniel F.; Buchheit, Kathleen M.; Boyce, Joshua; Barrett, Nora A.; Laidlaw, Tanya M.; Carroll, Shaina L.; Colonna, Lucrezia; Tkachev, Victor; Yu, Alison; Zheng, Henqi Betty; Gideon, Hannah P.; Winchell, Caylin G.; Lin, Philana Ling; Berger, Bonnie; Leslie, Alasdair; Flynn, JoAnne L.; Fortune, Sarah M.; Finberg, Robert W.; Kean, Leslie S.; Garber, Manuel; Schmidt, Aaron; Lingwood, Daniel; Shalek, Alex K.; Ordovás-Montañés, José; Network, HCA Lung Biological

doi:10.2139/ssrn.3555145

Cited by 172 publications

(293 citation statements)

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“…While such analyses cannot address molecular compatibility (due to sequence variation in ACE2 across species, as shown for lower compatibility of SARS-CoV and mouse ACE2 98 ), they can help determine if dual-positive cells are present in commonly employed models, and if their characteristics, proportions, and programs are similar to those of their human counterparts. In a separate study 46 , our lung network showed strong similarities to the human data in a macaque model. Here, we focused on the more distant, but commonly used, mouse model.…”

Section: Conserved Expression Patterns In Mouse Modelsmentioning

confidence: 57%

“…Our cross-tissue analysis substantially expands on our 45, 46,58,112 and others' [113][114][115] earlier efforts, allowing us to identify cell subsets across diverse tissues that may be implicated in virus transmission, pathogenesis, or both. Focusing on pathogenesis, in addition to key subsets in the lung, airways and gut, we identified ACE2 + cells that co-express either TMPRSS2 or CTSL in diverse organs, many of which have been associated with severe disease.…”

Section: Discussionmentioning

confidence: 99%

“…Importantly, ACE2 is particularly lowly expressed in young pediatric samples, also mirrored by lack of chromatin accessibility in the ACE2 locus. ACE2 expression is known to be regulated in complex ways across different tissues and may be affected by both common therapies (ACEi/ARB) (Tucker et al, companion manuscript 58 ), and during infection 46 . Moreover, both higher ACE2 expression per cell and a higher fraction of ACE2 + cells can in principle have implications for infection, but may have conflicting effects on pathogenesis, as ACE2 knockout mice show more severe ARDS upon lung injury because of its role in the renin-angiotensin pathway, which seems to protect from consequences of lung injury and inflammation 148 (for potential roles of this pathway on CoV infection (pre-COVID) see the review in 149 ).…”

Section: Discussionmentioning

confidence: 99%

“…Our Human Lung Cell Atlas analyses have revealed immune signaling genes that co-vary with ACE2 and TMPRSS2 in airway and lung cells 45, 46 . These analyses identified antiviral response genes that are enriched in ACE2 + TMPRSS2 + cells (e.g., IDO1, IRAK3, NOS2, TNFSF10, OAS1, MX1), and suggested that ACE2 itself is interferon regulated 45, 46 .…”

Section: An Immune Gene Program Associated With Ace2 + Tmprss2 + Exprmentioning

confidence: 99%

“…Identifying putative target cells in other organs could inform our understanding of extra-pulmonary COVID-19 associated organ failure or of potential placental transmission. Early analyses of the Human Lung Cell Atlas revealed that some of the cells of the nasal passages, airways, alveoli, and gut co-express ACE2 and TMPRSS2 45, 46 .…”

Section: Introductionmentioning

confidence: 99%

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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

Muus

Luecken

Eraslan

et al. 2020

Preprint

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244

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The COVID-19 pandemic, caused by the novel coronavirus SARS-CoV-2, creates an urgent need for identifying molecular mechanisms that mediate viral entry, propagation, and tissue pathology. Cell membrane bound angiotensin-converting enzyme 2 (ACE2) and associated proteases, transmembrane protease serine 2 (TMPRSS2) and Cathepsin L (CTSL), were previously identified as mediators of SARS-CoV2 cellular entry. Here, we assess the cell type-specific RNA expression of ACE2, TMPRSS2, and CTSL through an integrated analysis of 107 single-cell and single-nucleus RNA-Seq studies, including 22 lung and airways datasets (16 unpublished), and 85 datasets from other diverse organs. Joint expression of ACE2 and the accessory proteases identifies specific subsets of respiratory epithelial cells as putative targets of viral infection in the nasal passages, airways, and alveoli. Cells that co-express ACE2 and proteases are also identified in cells from other organs, some of which have been associated with COVID-19 transmission or pathology, including gut enterocytes, corneal epithelial cells, cardiomyocytes, heart pericytes, olfactory sustentacular cells, and renal epithelial cells. Performing the first meta-analyses of scRNA-seq studies, we analyzed 1,176,683 cells from 282 nasal, airway, and lung parenchyma samples from 164 donors spanning fetal, childhood, adult, and elderly age groups, associate increased levels of ACE2, TMPRSS2, and CTSL in specific cell types with increasing age, male gender, and smoking, all of which are epidemiologically linked to COVID-19 susceptibility and outcomes. Notably, there was a particularly low expression of ACE2 in the few young pediatric samples in the analysis. Further analysis reveals a gene expression program shared by ACE2 + TMPRSS2 + cells in nasal, lung and gut tissues, including genes that may mediate viral entry, subtend key immune functions, and mediate epithelial-macrophage cross-talk. Amongst these are IL6, its receptor and co-receptor, IL1R, TNF response pathways, and complement genes. Cell type specificity in the lung and airways and smoking effects were conserved in mice. Our analyses suggest that differences in the cell type-specific expression of mediators of SARS-CoV-2 viral entry may be responsible for aspects of COVID-19 epidemiology and clinical course, and point to putative molecular pathways involved in disease susceptibility and pathogenesis.

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Section: Conserved Expression Patterns In Mouse Modelsmentioning

confidence: 57%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: An Immune Gene Program Associated With Ace2 + Tmprss2 + Exprmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

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

Muus

Luecken

Eraslan

et al. 2020

Preprint

Self Cite

244

324

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Nasal ACE2 Levels and COVID-19 in Children

Patel

Verma

2020

JAMA

130

102

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Coronavirus disease 2019 (COVID-19) has disproportionately affected certain vulnerable populations. Studies noted higher rates of certain comorbidities such as hypertension, diabetes mellitus, and chronic obstructive pulmonary disease in patients infected with COVID-19 with severe disease. 1 Additionally, areas with more racial/ethnic minorities and higher rates of poverty have been shown to have higher rates of COVID-19 hospitalization and death. 2 After adjustment for comorbidities, age has been independently associated with increased mortality due to COVID-19. 3 However, limited attention has been given to children, who appear to have lower risk of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and mortality.In this issue of JAMA, Bunyavanich et al 4 identify a possible factor that may be related to lower rates of SARS-CoV-2 infection in children. The authors evaluated gene expression in nasal epithelial samples collected as part of a study involving patients with asthma from 2015 to 2018. The nasal epithelium is one of the first sites of infection with SARS-CoV-2, and the investigators probed for the expression of the cell surface enzyme angiotensin-converting enzyme 2 (ACE2), which has been proven to bind to SARS-CoV-2 spike protein and promote internalization of the virus into human cells. 5 Among a cohort of 305 patients aged 4 to 60 years, older children (10-17 years old; n = 185), young adults (18-24 years old; n = 46), and adults (≥25 years old; n = 29) all had higher expression of ACE2 in the nasal epithelium compared with younger children (4-9 years old; n = 45), and ACE2 expression was higher with each subsequent age group after adjusting for sex and asthma.Numerous studies have highlighted the low rates of SARS-CoV-2 infection in children compared with adults. Children have been shown to have fewer and less severe symptoms compared with adults. 6,7 This leads to the question of whether low rates of SARS-CoV-2 infection in children are due to low rates of testing in children, or if children are less susceptible to infection. An evaluation of 1286 close contacts of index cases in China found that infection rates in children were comparable with or slightly higher than in younger adults (aged 30-49 years) but were significantly lower than in older patients (aged ≥60 years). 8 This finding suggests that children seem to have similar rates of becoming infected compared with middle-aged adults following close contact with a person infected with SARS-CoV-2. In contrast, a targeted screening approach in Iceland found SARS-CoV-2 in 6.7% of children younger than 10 years old (n = 564) compared with in 13.7% of people aged 10 years or older (n = 8635). A population-wide screening approach not

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