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Authors: “Wang et al”

Link to paper: https://www.biorxiv.org/content/10.1101/2020.03.29.013490v1.full.pdf

Journal/ Pre-Print: biorxiv

Key Words: intestine, viral entry, defensin, innate immune system, ACE2

Research Highlights 

1. Dose-dependent preventive effect of HD5 on 2019-nCoV binding to IECs

2. Unravelled intestinal protection mechanism against 2019-nCoV infection

3. Addressed structural binding of 2019-nCoV1 S1 and HD5 to ACE2

Summary

Wang et al aimed to characterise the ACE2 receptor interaction with 2019-nCoV specifically in the intestine. Despite abundancy of ACE2 on intestinal epithelial cells, the occurrence of intestinal symptoms is low, hinting at an innate defence mechanism. They identified human defensin 5 (HD5), secreted by Paneth cells, to bind ACE2 and subsequently weakening recruitment of 2019-nCoV spike protein S1. Furthermore, they used the structure of ACE2 and HD5 at a resolution of 2.45 A°, to determine critical sites for 2019-nCoV S1 binding. Their findings imply that the binding affinity alone is insufficient to predict the therapeutic potential of drugs.

Impact for SARS-CoV2/COVID19 research efforts

Understand the immune response to SARS-CoV2/COVID19: explored the reason why the intestine is infected less

Understand the virology and/or cell biology of SARS-CoV2/COVID19: they addressed the binding of 2019-nCoV S1 to ACE2

Treat of SARS-CoV2/COVID19 positive individuals: potential drug treatment by increase of content of HD5 in vivo /design of HD5 related antibody/inhibitor, although this would have to be shown in the lung

Study Type

· In vitro study

· Structural biology

Strengths and limitations of the paper

Novelty: Innate immune defence mechanism against 2019-nCoV S1 binding of ACE2 in the intestine

Standing in the field: Not controversial

Appropriate statistics: they don’t report what statistical tests were performed

Viral model used: 2019-nCoV S1 was used for binding affinity studies

Translatability: Supplementation with HD5 could potentially prevent viral entry, but since its infection route is mainly via airways, the question remains if it could similarly work there (and also how to get it there. 

Main limitations: Intestinal “protection” interesting approach to solve viral entry, limitations are in applicability to lung

The affinity of HD5 binding to S1 is good but HD5 has less of an effect on ACE2-S1 interaction

Western blot densitometry not v reliable if bands reach saturation which is hard to tell

They use a colonic cell line, Paneth cells are in the small intestine

They underreport diarrhoea – estimates are 10%