SARS-CoV-2 receptor ACE2 is an interferon-stimulated gene in human airway epithelial cells and is enriched in specific cell subsets across tissues

Authors: Carly G. K. Ziegler et al.

Link to paper: https://papers.ssrn.com/sol3/papers.cfm?abstract_id=3555145

Journal/ Pre-Print: CellPress Sneak Peak

Key Words: single-cell RNA-seq, interferons

Research Highlights 

1. Discovered subpopulation of cells expressing ACE2 and TMPRSS2 in single-cell RNA-sequencing (scRNA-Seq) datasets including: a) type II pneumocytes in Non-human primate (NHP) and human lung tissue, b) absorptive enterocytes in NHP and human ileum, and c) goblet secretory cells in human upper airway nasal and sinus tissue and human nasal washes.

2. Found expression of interferon-responsive genes in cell populations expressing ACE2 and TMPRSS2 versus cell populations not expressing these genes in some of the scRNA-Seq datasets.

3. Discovered ACE2 as an interferon-responsive gene in human nasal epithelial cells using in-vitro experiments and a scRNA-Seq study of individuals with confirmed influenza.

Summary 

The authors examine ACE2 expression in scRNA-Seq data from non-human primate and human tissues (both healthy and infected with non-covid-19 viruses). They describe ACE2 and TMPRSS2 are co-expressing epithelial cells subsets including pneumocytes, ileal absorptive enterocytes, and nasal goblet secretory cells. Several investigations suggest that Type I interferons upregulate ACE2 expression, as indicated by an IFN-induced gene signature observed in ACE2-expressing human goblet secretory cells, in-vitro evidence of upregulation of ACE2 in human upper airway basal cells when treated with IFNs, and increased ACE2 expression in nasal goblet secretory cells with influenza infection, among other presented evidence.

Impact for SARS-CoV2/COVID19 research efforts

Understand the virology and/or cell biology of SARS-CoV2/COVID19

Found subpopulation of cells expressing ACE2 and TMPRSS2 in different tissues, which provide information on the virus possible entry points in tissues 

Treat of SARS-CoV2/COVID19 positive individuals

Treatment of patient with interferons could promote expression of ACE2, resulting in a higher number of cells which could be infected by SARS-CoV-2.

Study Type

· In silico study / bioinformatics study: single cell RNA-seq

· In vitro study: human and primate tissues.

Strengths and limitations of the paper

Novelty: Proposes ACE2 as an interferon-stimulated gene (ISG)

Standing in the field: Given its absence in peripheral blood mononuclear cells, ACE2 may have been missed as an ISG. However, multiple datasets from epithelial cells provide some evidence that ACE may be regulated by interferons.

Appropriate statistics: Only a small proportion of cells in the studied populations with scRNA-Seq do express ACE2, which may weaken the conclusions of the IFN signatures described in those datasets. Also, some tissues were not prepared to investigate epithelial cells, which result in an underrepresentation of these cells.

Viral model used: Various non-covid-19 viruses (influenza, HIV)

Translatability: May contribute to the search of potential targets for drug inhibitors of SARS-CoV-2 infection. Results may help to understand how IFN therapy for SARS-CoV-2 may be protective but also play a role in infection by increasing the expression of the viral receptor ACE2.

Main limitations: The direct link between SARS-CoV-2, interferon response, ACE2 upregulation, and the use of this mechanism by the virus to enhance infection still need to be investigated.