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Gastroenterology ; 160(3): 925-928.e4, 2021 02.
Article in English | MEDLINE | ID: covidwho-1575253
Gastroenterology ; 160(3): 925-928.e4, 2021 02.
Article in English | MEDLINE | ID: covidwho-977281
Virology ; 552: 43-51, 2021 01 02.
Article in English | MEDLINE | ID: covidwho-843443


This study focused on intestinal restitution including phenotype switching of absorptive enterocytes and the abundance of different enterocyte subtypes in weaned pigs after porcine epidemic diarrhea virus (PEDV) infection. At 10 days post-PEDV-inoculation, the ratio of villus height to crypt depth in both jejunum and ileum had restored, and the PEDV antigen was not detectable. However, enterocytes at the villus tips revealed epithelial-mesenchymal transition (EMT) in the jejunum in which E-cadherin expression decreased while expression of N-cadherin, vimentin, and Snail increased. Additionally, there was reduced expression of actin in microvilli and Zonula occludens-1 (ZO-1) in tight junctions. Moreover, the protein concentration of transforming growth factor ß1 (TGFß1), which mediates EMT and cytoskeleton alteration, was increased. We also found a decreased number of Peyer's patch M cells in the ileum. These results reveal incomplete restitution of enterocytes in the jejunum and potentially impaired immune surveillance in the ileum after PEDV infection.

Coronavirus Infections/veterinary , Enterocytes/pathology , Epithelial-Mesenchymal Transition , Gastroenteritis, Transmissible, of Swine/pathology , Peyer's Patches/pathology , Porcine epidemic diarrhea virus/pathogenicity , Animals , Cadherins/metabolism , Coronavirus Infections/immunology , Coronavirus Infections/pathology , Coronavirus Infections/virology , Gastroenteritis, Transmissible, of Swine/immunology , Gastroenteritis, Transmissible, of Swine/virology , Ileum/immunology , Ileum/pathology , Intestinal Mucosa/pathology , Jejunum/immunology , Jejunum/pathology , Microvilli/pathology , Swine , Tight Junctions/pathology , Transforming Growth Factor beta1/metabolism , Weaning
J Crohns Colitis ; 15(3): 485-498, 2021 Mar 05.
Article in English | MEDLINE | ID: covidwho-756892


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.

Angiotensin-Converting Enzyme 2/immunology , COVID-19 , Colitis, Ulcerative , Colon , Crohn Disease , Hepatocyte Nuclear Factor 4 , Ileum , Interferons/immunology , SARS-CoV-2/physiology , Biopsy/methods , COVID-19/immunology , COVID-19/pathology , COVID-19/physiopathology , Colitis, Ulcerative/immunology , Colitis, Ulcerative/pathology , Colitis, Ulcerative/virology , Colon/immunology , Colon/pathology , Colon/virology , Crohn Disease/immunology , Crohn Disease/pathology , Crohn Disease/virology , Cytokines/immunology , Female , Gene Expression Regulation , Hepatocyte Nuclear Factor 4/genetics , Hepatocyte Nuclear Factor 4/immunology , Humans , Ileum/immunology , Ileum/pathology , Ileum/virology , Male , Middle Aged , Sequence Analysis, RNA , Signal Transduction , Single-Cell Analysis