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Authors: Blume, CorneliaJackson et al. 

Journal/ Pre-Print:Biorxiv 

Tags: Cell Biology, Inflammation, Molecular biology, Virology 

Research Highlights 

  1. The researchers have identified a novel short isoform of angiotensin-converting enzyme 2 (ACE2) – termed “short ACE2” which is present in airways, particularly in ciliated cells of the nasal and bronchial epithelium. 

  1. Short ACE2 is lacking the SARS-CoV-2 binding sites 

  1. In primary airway cells, short ACE2 was also upregulated in response to treatment with IFN-beta treatment and infection with respiratory rhinovirus, but not infection with SARS-CoV-2. 

Summary

This preprint identifies a novel short isoform of ACE2 (short ACE2). The full isoform of ACE2 is expressed in multiple tissues whereas the short ACE2 transcript was detected exclusively in airways, liver and kidney, with highest expression in primary respiratory epithelia. The function of short ACE2 remains unknown although the authors speculate it may be involved in amino acid transport and report that is missing key residues required for SARS-CoV-2 bindingIn primary airway cells, short ACE2 was also upregulated in response to treatment with IFN-beta treatment and infection with respiratory rhinovirus, but not infection with SARS-CoV-2. 

Impact for SARS-CoV2/COVID19 research efforts  

Understand the immune response to SARS-CoV2/COVID19 – Short ACE2 was upregulated more robustly in response to rhinovirus than long ACE2 but neither isoform was upregulated in response to SARS-CoV-2 infection. This discrepancy may be due to the ability of coronaviruses, including SARS-CoV-2 to inhibit interferon signalling which the short isoform is induced by. 

Correlates of protection against SARS-CoV2/COVID19 infection – It has been reported that patients with asthma have reduced susceptibility to SARS-CoV-2. Bronchial samples from patients with severe asthma showed decreased long ACE2 levels but not short ACE2 leading the authors to suggest that suppression of long ACE2, alongside maintenance of short ACE2 expression is protective against SARS-CoV-2 infection in severe asthmatics. 

Study Type  

  • In vitro study 

Strengths and limitations of the paper 

Novelty: Identification of a shortened isoform of ACE2 which does not bind SARS-CoV-2 and is IFN sensitive, which has unknown functions. 

Standing in the field:Recent pre-print publications from independent sources have also identified a similar isoform of ACE2 in primates (https://www.biorxiv.org/content/10.1101/2020.07.19.210955v1) and reported that the primate isoform is also IFN sensitive but that (unlike this human short ACE2) this isoform is induced upon SARS-CoV2 infection. Differential isoforms of ACE2 have been reported in a number of species previously so identification in humans is promising (https://portlandpress.com/clinsci/article/134/10/1143/224978/Alternative-splicing-of-ACE2-possibly-generates). Another preprint by Ng et al. also reports similar findings of a human isoform of ACE2 which is lacking binding of SARS-CoV-2 and is IFN stimulated further bolstering these findings (https://www.biorxiv.org/content/10.1101/2020.07.24.219139v1) 

The connection between asthmatic patients, short ACE2 expression, and SARS-CoV-2 protection still remains speculative (at the authors own admission) although this presents a compelling future direction for research. 

Appropriate statistics:Appropriate statistics are used 

Viral model used:SARS-CoV-2 and Rhinovirus 16 

Translatability:The isolation of primary samples from chronic asthmatic patients provides increased clinical relevance, particularly when considering that asthmatic patients have reduced susceptibility to SARS-CoV-2 infection and is in contrast to many papers studying ACE2 which rely upon less clinically relevant cells such as Vero cells. The findings that this novel isoform of ACE2 is interferon stimulated coupled with the findings that SARS-CoV-2 cannot bind to short ACE2 provide a rationale for interferon-based treatments for SARS-CoV-2. 

Main limitations: The function of ACE2 remains uncertain however this is beyond the scope of this paper and the authors do attempt to identify a speculative function. Cell surface expression of short ACE2 is not demonstrated. It would be interesting to learn whether the short ACE2 affects virus entry mediated by long ACE2.