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

Over the past two decades, we have seen the emergence of three coronavirus outbreaks from zoonotic transmissions: severe acute respiratory syndrome (SARS)‑CoV, Middle East respiratory syndrome (MERS)‑CoV and SARS‑CoV‑2. The WHO defines zoonoses as ‘diseases and infections that are naturally transmitted between vertebrate animals and humans’. These novel coronaviruses cause acute respiratory illnesses with variable levels of pathogenicity and infectivity. As SARS‑CoV‑2 continues to spread worldwide, there is an ever-increasing urgency to fully comprehend the pathogenesis of the virus which causes the disease COVID‑19. Previous studies carried out in 2003 during the initial SAR‑CoV epidemic, showed that the human host factor angiotensin-converting Enzyme 2 (ACE2) acts as a receptor for SAR‑CoV (Li et al., 2003). The spike (S) protein in SARS‑CoV‑2 has been identified as having a higher affinity than SARS‑CoV in binding to ACE2. The principal host protease, 2 transmembrane serine protease (TMPRSS2), mediates S protein activation on primary target cells and allows viral entry (Glowacka, S et al., 2011).

In this paper, Ziegler et al. (2020), used single-cell RNA‑seq (scRNA‑seq) data to analyse human, non-human primate (NHP) and mouse barrier tissues to identify putative SARS‑CoV‑2 targets. Their methods highlight how the various samples and tissues from model organisms were collected and prepared for scRNA‑seq. scRNA‑seq was performed using Seq‑Well v1 and S3, 10X chromium v2 3’ and Drop‑seq. Smart‑Seq2 was used for Bulk RNA‑seq along with cell cytokine stimulation. An additional method of Western blot was used for human ACE2.

Meta-analysis of human, NHPs, and mouse scRNA‑seq datasets for putative SARS‑CoV‑2 targets showed:

Data showing that expression of the cellular entry receptor for SARS‑Cov‑2, ACE2, is primarily restricted to type II pneumocytes in the lung, absorptive enterocytes within the gut, and nasal secretory cells. They were shown as ACE2+TMPRSS2+.

Parallels in cellular identities and frequencies of putative SAR‑CoV‑2 target cells across human and NHP cohort.

Identification of ACE2 as a human interferon-stimulated gene (ISG) in vitro using airway epithelial cells. They then developed this discovery to in vivo viral infections.

Increased expression of ACE2 during Simian immunodeficiency virus (SHIV) and Tuberculosis (TB) infections of NHPs and HIV/TB co-infection and influence infection of humans compared to controls.

Results suggesting that SARS‑CoV‑2 may utilise species-specific interferon-driven upregulation of ACE2, a tissue-protective mediator during lung damage, to increase infection.

That mouse ACE2 showed no upregulation by interferon, therefore, raising prospective implications for disease modelling.

This paper emphasizes the power of scRNA‑seq datasets in establishing hypothesises applicable to human disease that may differ from concepts formed using cell lines. The results identified ACE2 as an ISG, alluding to the balance between tissue tolerance and viral infection required at the human airway epithelium. The authors acknowledge the need for continued collaborative efforts from scientists worldwide in determining how SARS‑CoV‑2 influences host response as well as understanding the hosts potential resistance or tolerance mechanisms.

References

Ziegler CGK, Allon SJ, Nyquist SK, et al. SARS‑CoV‑2 Receptor ACE2 Is an Interferon-Stimulated Gene in Human Airway Epithelial Cells and Is Detected in Specific Cell Subsets across Tissues. 2020, Cell 181, 1016-1035
https://doi.org/10.1016/j.cell.2020.04.035

W. Li, M.J. Moore, N. Vasilieva, J. Sui, S.K. Wong, M.A. Berne, M. Somasundaran, J.L. Sullivan, K. Luzuriaga, T.C. Greenough, et al. Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus. Nature 426, 450‑454(2003)

Glowacka, S. Bertram, M.A. Müller, P. Allen, E. Soilleux, S. Pfefferle, I. Steffen, T.S. Tsegaye, Y. He, K. Gnirss, et al. Evidence that TMPRSS2 Activates the Severe Acute Respiratory Syndrome Coronavirus Spike Protein for Membrane Fusion and Reduces Viral Control by the Humoral Immune Response. J. Virol., 2011 85 (9), pp. 4122‑4134
https://doi.org/10.1128/JVI.02232-10

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