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Authors: Mayte Suárez-Fariñas, Minami Tokuyama, Gabrielle Wei, Ruiqi Huang, Alexandra Livanos, Divya Jha, Anais Levescot, Roman Kosoy, Haritz Irizar, Sascha Cording, Wenhui Wang, Ryan Ungaro, Antonio Di’Narzo, Gustavo Martinez, Maria Suprun, Michael J. Corley, Aleksandar Stojmirovic, Sander M. Houten, Mark Curran, Carrie Brodmerkel, Jacqueline Perrigoue, Joshua R. Friedman, Ke Hao, Eric E. Schadt, Jun Zhu, Huaibin M. Ko, Judy Cho, Marla C. Dubinsky, Bruce E. Sands, Lishomwa Ndhlovu, Nadine Cerf-Benssusan, Andrew Kasarskis, Jean Frederic Colombel, Noam Harpaz, Carmen Argmann, Saurabh Mehandru

Link to paper: https://www.biorxiv.org/content/10.1101/2020.05.21.109124v1.full.pdf

Journal/ Pre-Print: bioRxiv

Tags: Immunology/Immunity, Bioinformatics

Research Highlights 

1. ACE2 expression high in small intestine in contrast to TMPRSS2 expression pre-dominantly found in colon.

2. Common IBD medications do not have a major impact on gene expression of ACE2 or TMPRSS2.

3. Genes expressed during SARS-COV2 lung infection (in vitro stimulations) also detected in inflamed intestinal biopsies (whole tissue) with IFN- and IL-6 signalling shared among both pathologies.

Summary

This goal of this publication was to examine the areas of intersection between the uninflamed and inflamed GI tract and COVID-19. The paper highlights a higher expression of ACE2 in the healthy ileum compared to the colon and in contrast increased levels of TMPRSS2 in the colon. Inconsistency arises when expression of both proteins is probed in healthy, inflamed and treated (biological and non-biological) IBD patients with merely minor changes in expression patterns observed. By comparing epithelial gene signatures curated from SARS-COV2 exposed cells with IBD- associated gene signatures the authors further find shared gene networks between both pathologies, in particular IFN- and IL-6 associated pathways. 

Impact for SARS-CoV2/COVID19 research efforts

· Treatment of SARS-CoV2/COVID19 positive individuals (Assessment if drugs used in IBD therapeutics could also treat the inflammatory aspects of COVID-19 due to a possible overlap of cytokine networks/mechanisms such as IL-6)

Study Type

· In silico study / bioinformatics study

· Clinical Cohort study (e.g. drug trials)

· Patient Case study

Strengths and limitations of the paper

Novelty (controversial):

· Assessment of ACE2/ TMPRSS2 on protein level by immunofluorescence along the human colon and the impact of inflammation and common IBD drugs on their expression. (However, staining is (in part) inconsistent with in silico data).

· Identification of regulatory gene networks associated with ACE2/TMPRSS2 expression in intestinal biopsies.

· In silico overlap study between COVID-19 treated lung cells and inflamed intestinal diseases show IL-6 and other innate pathways shared by both pathologies. (However, not an unpredictable/novel finding).

Standing in the field:

· Whilst comparing IBD and Covid gene signatures is novel, the main finding that both signatures show a strong IL-6 and IFN response is not very surprising given the previous literature on these pathways in both diseases.

Appropriate statistics: Significant detail on methods (and sample sizes) is restricted to the supplementary methods, which do not appear to be available online.

Translatability:

· Due to communality of IFN and IL-6 pathways playing a role in both pathologies, treatments validated for IBD patients can potentially be used in COVID-19 clinical trials (which is ongoing for IL-6).

Main limitations:

· Homogenous immunofluorescent ACE2 staining of the ileum unexpected. Optimised and well controlled staining needed to verify true apical intestinal epithelial cell staining.

· A variety of inconsistency between results, hinting to marginal differences seen between conditions merely due to noise in data.

· Whilst the different IBD treatments analysed indicated small differences in receptor expression between drugs used, the prevalence of severe Covid-19 in IBD patients appears to be reduced in those taking biologics compared with those taking corticosteroids (where it is unclear whether there is in fact a negative effect). Given the relative similarities between ACE2/TMPRSS expression shown here, this suggests that any protective effect of these drugs is not through modulation of receptor expression.