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Authors: Lee, I. et al.

Link to paper: https://doi.org/10.1101/2020.05.08.20092866

Journal/ Pre-Print: medRxiv

Tags: Bioinformatics, Cell Biology, Molecular biology, Patient cohort

Research Highlights 

1. The SARS-CoV-2 receptor ACE2 was expressed in the motile cilia of human upper and lower respiratory tract epithelia

2. ACE2 expression at the cilium in nasal tissue was not affected by age, sex or smoker status

3. Use of ACE inhibitors or angiotensin receptor blockers was not associated with increased ciliary ACE2 expression in nasal tissue samples relative to controls

Summary

The authors found that the SARS-CoV-2 receptor ACE2 was expressed in human respiratory tract samples, and was enriched in the motile cilia organelle, which was therefore proposed as a potential site of virus entry. Ciliary ACE2 expression in nasal tissues did not correlate with age, sex or smoker status of human donors. This was also unaffected in samples from patients taking ACE inhibitors (ACEI) or angiotensin receptor blockers (ARBs), which have been linked to increase susceptibility to SARS-CoV-2 infection through upregulation of ACE2. The authors therefore suggest that the endogenous function of ACE2 in the cilia may be distinct from its role in the renin-angiotensin-aldosterone system.

Impact for SARS-CoV2/COVID19 research efforts

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

Inhibit SARS-CoV2/COVID19 transmission (discovery of ACE2 localisation at the cilium provides a platform for future functional studies, and provides a potential mechanism of SARS-CoV-2 viral entry that could be therapeutically targeted to modulate SARS-CoV-2 infection).

Treatment of hypertension in patients may continue without increasing susceptibility to SARS-CoV-2 infection (authors provide evidence that ACEI or ARB treatment does not increase susceptibility to SARS-CoV-2 infection, and therefore treatment should not be stopped in COVID19 patients).

Study Type

· In vitro study (ACE2 and cilia IHC in IMCD3 renal mouse cell line)

· In vivo study (staining of ACE2 and cilia in human tissue samples)

· Patient cohorts

Strengths and limitations of the paper

Novelty: Demonstrated that ACEI or ARB use does not increase ACE2 expression in cilia of human nasal tissue

Standing in the field: Confirms findings of other papers showing that ACE2 is expressed at relatively low levels in the respiratory tract, and that ACE2 localised to the cilium. Support the specificity of some commercially available antibodies by orthogonal validation which may also serve as a useful resource to help guide future protein-based studies. Do not see ACE2 expression in CD13-positive vascular endothelium or respiratory tract goblet cells, which contradicts previous RNA-seq studies

Appropriate statistics: Yes, thoroughly described. However, number of replicates in patient sample analysis limited and not always clear

Viral model used: None. The authors only looked at ACE2 expression.

Translatability: Confirms basic biology research for translational work. More research needed to confirm that ciliary ACE2 mediates SARS-CoV-2 viral entry and therefore is a potential therapeutic target for treating COVID19 patients. Some implications for treatment of comorbidities in COVID19 patients (i.e. ACEI and ARB use for treatment of hypertension is unlikely to increase risk of SARS-CoV-2 infection)

Main limitations: 1. As authors state, this is only an observational study of the correlation between ciliary ACE2 in nasal epithelia, and ACEI and ARB treatment

2. Limited sample numbers, particularly in some patient cohorts due to differing hypertension treatment routines between countries

3. Only use epifluorescence microscopy. Future use of higher resolution microscopy could give a better indication of where exactly ACE2 is and the potential mechanism of viral entry at the cilium.

4. Do not directly image SARS-CoV-2 at the cilium of infected tissue, only look at its putative receptor in tissue sections from previous patient cohorts