PT - JOURNAL ARTICLE AU - Bram Verstockt AU - Sare Verstockt AU - Saeed Abdu Rahiman AU - Bo-jun Ke AU - Kaline Arnauts AU - Isabelle Cleynen AU - João Sabino AU - Marc Ferrante AU - Gianluca Matteoli AU - Séverine Vermeire TI - Intestinal receptor of SARS-CoV-2 in inflamed IBD tissue is downregulated by HNF4A in ileum and upregulated by interferon regulating factors in colon AID - 10.1101/2020.06.24.169383 DP - 2020 Jan 01 TA - bioRxiv PG - 2020.06.24.169383 4099 - http://biorxiv.org/content/early/2020/06/24/2020.06.24.169383.short 4100 - http://biorxiv.org/content/early/2020/06/24/2020.06.24.169383.full AB - Patients with IBD are considered immunosuppressed, but do not seem more vulnerable for COVID-19. Nevertheless, intestinal inflammation has shown an important risk factor for SARS-CoV-2 infection and prognosis. Therefore, we investigated the effect of intestinal inflammation on the viral intestinal entry mechanisms, including ACE2, in IBD.We collected (un)inflamed mucosal biopsies from CD (n=193) and UC (n=158) patients, and 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-TNF therapy, were analyzed.In inflamed CD ileum, ACE2 was significantly decreased compared to control ileum (p=4.6E-07), whereas colonic ACE2 expression was higher in inflamed colon of CD/UC compared to 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, while pro-inflammatory cytokines and interferon regulating factors regulated colonic ACE2. Inflammatory stimuli upregulated ACE2 in UC organoids (p=1.7E-02), not in non-IBD controls (p=9.1E-01). Anti-TNF therapy restored colonic ACE2 dysregulation in responders.Intestinal inflammation alters SARS-CoV-2 coreceptors in the intestine, with opposing effects in ileum and colon. HNF4A, an IBD susceptibility gene, is an important upstream regulator of ACE2 in ileum, whereas interferon signaling dominates in colon. Our data support the importance of adequate control of IBD in order to reduce risk of (complicated) COVID-19.Competing Interest StatementB Verstockt reports financial support for research from Pfizer; lecture fees from Abbvie, Ferring, Takeda Pharmaceuticals, Janssen and R Biopharm; consultancy fees from Janssen and Sandoz. J Sabino reports lecture fees from Abbvie, Takeda, Janssen and Nestle Health Sciences. M Ferrante reports financial support for research: Amgen, Biogen, Janssen, Pfizer, Takeda, Consultancy: Abbvie, Boehringer-Ingelheim, MSD, Pfizer, Sandoz, Takeda and Thermo Fisher; Speakers fee: Abbvie, Amgen, Biogen, Boehringer-Ingelheim, Falk, Ferring, Janssen, Lamepro, MSD, Mylan, Pfizer, Sandoz, and Takeda. G Matteoli received financial support for research from DSM Nutritional Products, Karyopharm Therapeutics and Janssen. S Vermeire reports financial support for research: MSD, AbbVie, Takeda, Pfizer, JnJ; Lecture fee(s): MSD, AbbVie, Takeda, Ferring, Centocor, Hospira, Pfizer, JnJ, Genentech/Roche Consultancy: MSD, AbbVie, Takeda, Ferring, Centocor, Hospira, Pfizer, JnJ, Genentech/Roche, Celgene, Mundipharma, Celltrion, SecondGenome, Prometheus, Shire, Prodigest, Gilead, Galapagos. S Verstockt, S Abdu Rahiman, BJ Ke, K Arnouts and I Cleynen declare no conflicts of interest. ACEangiotensin converting enzymeadjadjustedCOVID-19coronavirus disease 2019CDCrohn’s diseaseCRCcolorectal cancerDPP4dipeptidyl peptidase 4FCfold changeFDRfalse discovery rateHNF4Ahepatocyte nuclear factor 4 AlphaGEMgel beads in emulsionIBDinflammatory bowel diseaseIFNinterferonILinterleukinIPAingenuity pathway analysisIQRinterquartile rangeMAFminor allele frequencyMERSmiddle east respiratory syndromeRASrenin-angiotensinogen systemRNAribonucleic acidSARSsevere acute respiratory syndromeSCENICSingle Cell Network InferenceTMPRSStransmembrane protease serineTNFtumour necrosis factorUCulcerative colitisWGCNAweighted gene co-expression network analysis