Intestinal Receptor of SARS-CoV-2 in Inflamed IBD Tissue Seems Downregulated by HNF4A in Ileum and Upregulated by Interferon Regulating Factors in Colon.
Intestinal Receptor of SARS-CoV-2 in Inflamed IBD Tissue Seems Downregulated by HNF4A in Ileum and Upregulated by Interferon Regulating Factors in Colon.
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DOI：
10.1093/ecco-jcc/jjaa185
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发表时间：
2021-03-05
期刊：
影响因子：
--
通讯作者：
Vermeire S
中科院分区：
文献类型：
--
作者：
Verstockt B;Verstockt S;Abdu Rahiman S;Ke BJ;Arnauts K;Cleynen I;Sabino J;Ferrante M;Matteoli G;Vermeire S
炎症性肠病[IBD]患者被认为是免疫抑制的，但似乎并不更容易感染COVID-19。然而，肠道炎症已被证明是SARS-CoV-2感染和预后的重要危险因素。因此，我们研究了IBD中肠道炎症对病毒肠道进入机制（包括ACE 2）的作用。我们从克罗恩病[CD] [n = 193]和溃疡性结肠炎[UC] [n = 158]患者以及51名匹配的非IBD对照中收集了炎症和非炎症粘膜活检组织，用于RNA测序、差异基因表达和共表达分析。 来自UC患者的类器官经受炎性混合物并进行RNA测序处理。对回肠回肠活检进行单细胞[sc]测序。分析了公开的结肠sc-RNA测序数据和抗肿瘤坏死因子[TNF]治疗前/后组织的微阵列。在发炎的CD回肠中，与对照回肠相比，ACE 2显著降低[p = 4.6E-07]，而与对照相比，CD/UC的发炎结肠中的结肠ACE 2更高[p = 8.3E-03; p = 1.9E-03]。 Sc-RNA测序证实了这种ACE 2失调和排他性上皮ACE 2表达。网络分析强调HNF 4A是回肠ACE 2的关键调节因子，促炎细胞因子和干扰素调节因子调节结肠ACE 2。炎症刺激上调UC类器官中的ACE 2 [p = 1.7E-02]，但在非IBD对照中则不然[p = 9.1E-01]。 抗TNF治疗恢复了应答者的结肠ACE 2调节。肠道炎症改变了肠道中的SARS-CoV-2辅助受体，回肠和结肠中的调节障碍相反。IBD易感基因HNF 4A在回肠中似乎是ACE 2的重要上游调节因子，而干扰素信号可能在结肠中占主导地位。
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. 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. 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. 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.
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DOI：
10.1093/bioinformatics/btu638
发表时间：
2015-01-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Anders S;Pyl PT;Huber W
通讯作者：
Huber W
ACE2将氨基酸营养不良与微生物生态学和肠炎联系起来。
影响因子：
64.8
作者：
Hashimoto T;Perlot T;Rehman A;Trichereau J;Ishiguro H;Paolino M;Sigl V;Hanada T;Hanada R;Lipinski S;Wild B;Camargo SM;Singer D;Richter A;Kuba K;Fukamizu A;Schreiber S;Clevers H;Verrey F;Rosenstiel P;Penninger JM
通讯作者：
Penninger JM
影响因子：
168.9
作者：
Huang, Chaolin;Wang, Yeming;Cao, Bin
通讯作者：
Cao, Bin
影响因子：
56.9
作者：
Lamers, Mart M.;Beumer, Joep;Clevers, Hans
通讯作者：
Clevers, Hans
影响因子：
4.9
作者：
Ahn, Sung-Hoon;Shah, Yatrik M.;Inoue, Junko;Morimura, Keiichirou;Kim, Insook;Yim, SunHee;Lambert, Gilles;Kurotani, Reiko;Nagashima, Kunio;Gonzalez, Frank J.;Inoue, Yusuke
通讯作者：
Inoue, Yusuke