Cargando…

Intestinal Receptor of SARS-CoV-2 in Inflamed IBD Tissue Seems Downregulated by HNF4A in Ileum and Upregulated by Interferon Regulating Factors in Colon

BACKGROUND: Patients with inflammatory bowel disease [IBD] are considered immunosuppressed, but do not seem more vulnerable for COVID-19. Nevertheless, intestinal inflammation has shown to be an important risk factor for SARS-CoV-2 infection and prognosis. Therefore, we investigated the role of inte...

Descripción completa

Detalles Bibliográficos
Autores principales: Verstockt, Bram, Verstockt, Sare, Abdu Rahiman, Saeed, Ke, Bo-jun, Arnauts, Kaline, Cleynen, Isabelle, Sabino, João, Ferrante, Marc, Matteoli, Gianluca, Vermeire, Séverine
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7543339/
https://www.ncbi.nlm.nih.gov/pubmed/32915959
http://dx.doi.org/10.1093/ecco-jcc/jjaa185
_version_ 1783591692662734848
author Verstockt, Bram
Verstockt, Sare
Abdu Rahiman, Saeed
Ke, Bo-jun
Arnauts, Kaline
Cleynen, Isabelle
Sabino, João
Ferrante, Marc
Matteoli, Gianluca
Vermeire, Séverine
author_facet Verstockt, Bram
Verstockt, Sare
Abdu Rahiman, Saeed
Ke, Bo-jun
Arnauts, Kaline
Cleynen, Isabelle
Sabino, João
Ferrante, Marc
Matteoli, Gianluca
Vermeire, Séverine
author_sort Verstockt, Bram
collection PubMed
description BACKGROUND: Patients with inflammatory bowel disease [IBD] are considered immunosuppressed, but do not seem more vulnerable for COVID-19. Nevertheless, intestinal inflammation has shown to be an important risk factor for SARS-CoV-2 infection and prognosis. Therefore, we investigated the role of intestinal inflammation on the viral intestinal entry mechanisms, including ACE2, in IBD. METHODS: We collected inflamed and uninflamed mucosal biopsies from Crohn’s disease [CD] [n = 193] and ulcerative colitis [UC] [n = 158] patients, and from 51 matched non-IBD controls for RNA sequencing, differential gene expression, and co-expression analysis. Organoids from UC patients were subjected to an inflammatory mix and processed for RNA sequencing. Transmural ileal biopsies were processed for single-cell [sc] sequencing. Publicly available colonic sc-RNA sequencing data, and microarrays from tissue pre/post anti-tumour necrosis factor [TNF] therapy, were analysed. RESULTS: In inflamed CD ileum, ACE2 was significantly decreased compared with control ileum [p = 4.6E-07], whereas colonic ACE2 was higher in inflamed colon of CD/UC compared with control [p = 8.3E-03; p = 1.9E-03]. Sc-RNA sequencing confirmed this ACE2 dysregulation and exclusive epithelial ACE2 expression. Network analyses highlighted HNF4A as key regulator of ileal ACE2, and pro-inflammatory cytokines and interferon regulating factors regulated colonic ACE2. Inflammatory stimuli upregulated ACE2 in UC organoids [p = 1.7E-02], but not in non-IBD controls [p = 9.1E-01]. Anti-TNF therapy restored colonic ACE2 regulation in responders. CONCLUSIONS: Intestinal inflammation alters SARS-CoV-2 coreceptors in the intestine, with opposing dysregulations in ileum and colon. HNF4A, an IBD susceptibility gene, seems an important upstream regulator of ACE2 in ileum, whereas interferon signalling might dominate in colon.
format Online
Article
Text
id pubmed-7543339
institution National Center for Biotechnology Information
language English
publishDate 2020
publisher Oxford University Press
record_format MEDLINE/PubMed
spelling pubmed-75433392020-10-08 Intestinal Receptor of SARS-CoV-2 in Inflamed IBD Tissue Seems Downregulated by HNF4A in Ileum and Upregulated by Interferon Regulating Factors in Colon Verstockt, Bram Verstockt, Sare Abdu Rahiman, Saeed Ke, Bo-jun Arnauts, Kaline Cleynen, Isabelle Sabino, João Ferrante, Marc Matteoli, Gianluca Vermeire, Séverine J Crohns Colitis Original Articles BACKGROUND: Patients with inflammatory bowel disease [IBD] are considered immunosuppressed, but do not seem more vulnerable for COVID-19. Nevertheless, intestinal inflammation has shown to be an important risk factor for SARS-CoV-2 infection and prognosis. Therefore, we investigated the role of intestinal inflammation on the viral intestinal entry mechanisms, including ACE2, in IBD. METHODS: We collected inflamed and uninflamed mucosal biopsies from Crohn’s disease [CD] [n = 193] and ulcerative colitis [UC] [n = 158] patients, and from 51 matched non-IBD controls for RNA sequencing, differential gene expression, and co-expression analysis. Organoids from UC patients were subjected to an inflammatory mix and processed for RNA sequencing. Transmural ileal biopsies were processed for single-cell [sc] sequencing. Publicly available colonic sc-RNA sequencing data, and microarrays from tissue pre/post anti-tumour necrosis factor [TNF] therapy, were analysed. RESULTS: In inflamed CD ileum, ACE2 was significantly decreased compared with control ileum [p = 4.6E-07], whereas colonic ACE2 was higher in inflamed colon of CD/UC compared with control [p = 8.3E-03; p = 1.9E-03]. Sc-RNA sequencing confirmed this ACE2 dysregulation and exclusive epithelial ACE2 expression. Network analyses highlighted HNF4A as key regulator of ileal ACE2, and pro-inflammatory cytokines and interferon regulating factors regulated colonic ACE2. Inflammatory stimuli upregulated ACE2 in UC organoids [p = 1.7E-02], but not in non-IBD controls [p = 9.1E-01]. Anti-TNF therapy restored colonic ACE2 regulation in responders. CONCLUSIONS: Intestinal inflammation alters SARS-CoV-2 coreceptors in the intestine, with opposing dysregulations in ileum and colon. HNF4A, an IBD susceptibility gene, seems an important upstream regulator of ACE2 in ileum, whereas interferon signalling might dominate in colon. Oxford University Press 2020-09-11 /pmc/articles/PMC7543339/ /pubmed/32915959 http://dx.doi.org/10.1093/ecco-jcc/jjaa185 Text en © The Author(s) 2020. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation. http://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com
spellingShingle Original Articles
Verstockt, Bram
Verstockt, Sare
Abdu Rahiman, Saeed
Ke, Bo-jun
Arnauts, Kaline
Cleynen, Isabelle
Sabino, João
Ferrante, Marc
Matteoli, Gianluca
Vermeire, Séverine
Intestinal Receptor of SARS-CoV-2 in Inflamed IBD Tissue Seems Downregulated by HNF4A in Ileum and Upregulated by Interferon Regulating Factors in Colon
title Intestinal Receptor of SARS-CoV-2 in Inflamed IBD Tissue Seems Downregulated by HNF4A in Ileum and Upregulated by Interferon Regulating Factors in Colon
title_full Intestinal Receptor of SARS-CoV-2 in Inflamed IBD Tissue Seems Downregulated by HNF4A in Ileum and Upregulated by Interferon Regulating Factors in Colon
title_fullStr Intestinal Receptor of SARS-CoV-2 in Inflamed IBD Tissue Seems Downregulated by HNF4A in Ileum and Upregulated by Interferon Regulating Factors in Colon
title_full_unstemmed Intestinal Receptor of SARS-CoV-2 in Inflamed IBD Tissue Seems Downregulated by HNF4A in Ileum and Upregulated by Interferon Regulating Factors in Colon
title_short Intestinal Receptor of SARS-CoV-2 in Inflamed IBD Tissue Seems Downregulated by HNF4A in Ileum and Upregulated by Interferon Regulating Factors in Colon
title_sort intestinal receptor of sars-cov-2 in inflamed ibd tissue seems downregulated by hnf4a in ileum and upregulated by interferon regulating factors in colon
topic Original Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7543339/
https://www.ncbi.nlm.nih.gov/pubmed/32915959
http://dx.doi.org/10.1093/ecco-jcc/jjaa185
work_keys_str_mv AT verstocktbram intestinalreceptorofsarscov2ininflamedibdtissueseemsdownregulatedbyhnf4ainileumandupregulatedbyinterferonregulatingfactorsincolon
AT verstocktsare intestinalreceptorofsarscov2ininflamedibdtissueseemsdownregulatedbyhnf4ainileumandupregulatedbyinterferonregulatingfactorsincolon
AT abdurahimansaeed intestinalreceptorofsarscov2ininflamedibdtissueseemsdownregulatedbyhnf4ainileumandupregulatedbyinterferonregulatingfactorsincolon
AT kebojun intestinalreceptorofsarscov2ininflamedibdtissueseemsdownregulatedbyhnf4ainileumandupregulatedbyinterferonregulatingfactorsincolon
AT arnautskaline intestinalreceptorofsarscov2ininflamedibdtissueseemsdownregulatedbyhnf4ainileumandupregulatedbyinterferonregulatingfactorsincolon
AT cleynenisabelle intestinalreceptorofsarscov2ininflamedibdtissueseemsdownregulatedbyhnf4ainileumandupregulatedbyinterferonregulatingfactorsincolon
AT sabinojoao intestinalreceptorofsarscov2ininflamedibdtissueseemsdownregulatedbyhnf4ainileumandupregulatedbyinterferonregulatingfactorsincolon
AT ferrantemarc intestinalreceptorofsarscov2ininflamedibdtissueseemsdownregulatedbyhnf4ainileumandupregulatedbyinterferonregulatingfactorsincolon
AT matteoligianluca intestinalreceptorofsarscov2ininflamedibdtissueseemsdownregulatedbyhnf4ainileumandupregulatedbyinterferonregulatingfactorsincolon
AT vermeireseverine intestinalreceptorofsarscov2ininflamedibdtissueseemsdownregulatedbyhnf4ainileumandupregulatedbyinterferonregulatingfactorsincolon