Cytomegalovirus Infection Exacerbates Experimental Colitis by Promoting IL-23 Production

Xuan, Lingling; Ren, Lulu; Han, Feifei; Gong, Lili; Wan, Zhenzhen; Yang, Song; Li, He; Lv, Yali

doi:10.1007/s10753-019-01122-x

Cited by 8 publications

(6 citation statements)

References 31 publications

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“…Similarly, we observed HCMV-positive intestinal epithelial cells in an IBD patient associated with HCMV, but the existence of a correlation/association does not necessarily indicate causality. Nevertheless, CMV infection experiments in mouse models of IBD have shown that acute and latent CMV infection exacerbates intestinal inflammation [35][36][37][38]. Although the underlying mechanism are not entirely understood, it was demonstrated that concomitant MCMV infection increased gross bleeding [35], induced the production of pro-inflammatory cytokines or chemokine ligands in the colon [36,38], or stimulated gut immune responses to the gut microbiota [37].…”

Section: Discussionmentioning

confidence: 99%

Acute cytomegalovirus infection modulates the intestinal microbiota and targets intestinal epithelial cells

et al. 2022

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Primary and recurrent cytomegalovirus (CMV) infections frequently cause CMV colitis in immunocompromised as well as inflammatory bowel disease (IBD) patients. Additionally, colitis occasionally occurs upon primary CMV infection in patients who are apparently immunocompetent. In both cases, the underlying pathophysiologic mechanisms are largely elusive -in part due to the lack of adequate access to specimens. We employed the mouse cytomegalovirus (MCMV) model to assess the association between CMV and colitis. During acute primary MCMV infection of immunocompetent mice, the gut microbial composition was affected as manifested by an altered ratio of the Firmicutes to Bacteroidetes phyla. Interestingly, these microbial changes coincided with high-titer MCMV replication in the colon, crypt hyperplasia, increased colonic pro-inflammatory cytokine levels, and a transient increase in the expression of the antimicrobial protein Regenerating islet-derived protein 3 gamma (Reg3γ). Further analyses revealed that murine and human intestinal epithelial cell lines, as well as primary intestinal crypt cells and organoids represent direct targets of CMV infection causing increased cell death. Accordingly, in vivo MCMV infection disrupted the intestinal epithelial barrier and increased apoptosis of intestinal epithelial cells. In summary, our data show that CMV transiently induces colitis in immunocompetent hosts by altering the intestinal homeostasis.

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Section: Discussionmentioning

confidence: 99%

Acute cytomegalovirus infection modulates the intestinal microbiota and targets intestinal epithelial cells

et al. 2022

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“…Although the underlying mechanism are not entirely understood, it was demonstrated that concomitant MCMC infection increased gross bleeding [34], induced the production of proinflammatory cytokines or chemokine ligands in the colon [35,37], or stimulated gut immune responses to the gut microbiota [36].…”

Section: Discussionmentioning

confidence: 99%

“…Similarly, we observed HCMV positive intestinal epithelial cells in an IBD patient associated with HCMV, but the existence of a correlation/association does not necessarily inidcate causality. Nevertheless, CMV infection experiments in mouse models of IBD have shown that acute and latent CMV infection exacerbates intestinal inflammation [34–37]. Although the underlying mechanism are not entirely understood, it was demonstrated that concomitant MCMC infection increased gross bleeding [34], induced the production of pro-inflammatory cytokines or chemokine ligands in the colon [35, 37], or stimulated gut immune responses to the gut microbiota [36].…”

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Acute Cytomegalovirus Infection Modulates the Intestinal Microbiota and Targets Intestinal Epithelial Cells

Le‐Trilling

Ebel²,

Baier³

et al. 2022

Preprint

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Primary and recurrent cytomegalovirus (CMV) infections frequently cause CMV colitis in immunocompromised as well as inflammatory bowel disease (IBD) patients. Additionally, colitis occasionally occurs upon primary CMV infection in patients who are apparently immunocompetent. In both cases, the underlying pathophysiologic mechanisms are largely elusive - in part due to the lack of adequate access to specimens. We employed the mouse cytomegalovirus (MCMV) model to probe into the association between CMV and colitis. During acute primary MCMV infection of immunocompetent mice, the gut microbial composition was affected within the first 5 days post-infection as manifested by an altered ratio of the Firmicutes to Bacteroidetes phyla. Interestingly, these microbial changes incited with high-titer MCMV replication in the colon, mild crypt necrosis and increased colonic pro-inflammatory cytokine levels. Further analyses revealed that murine and human intestinal epithelial cell line as well as primary intestinal crypt cells/ organoids represent direct targets of CMV accompanied by increased cell mortality upon infection. Accordingly, in vivo MCMV infection disrupted the intestinal epithelial barrier and increased apoptosis of intestinal epithelial cells. In summary, our data show that CMV induces colitis in immunocompetent hosts by altering the intestinal homeostasis.

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“…Upon preventive administration of H1M1 the clinical score was reduced during DSS administration and post-DSS recovery (Figure 7F). H1M1 did not reduce severity of inflammation 18 (Figure 7G), but reduced development of fibrosis as measured by picrosirius red, FN1 and ColI staining (Figure 7H) and reduced muscularis propria thickening (Figure 7I). H1M1 also reduced gene expression of TNF and showed a trend for reduced IL6 expression (Figure 7J).…”

Section: Functional Ablation Of Cadherin-11 Improves Experimental Int...mentioning

confidence: 90%

Stricturing Crohn’s disease single-cell RNA sequencing reveals fibroblast heterogeneity and intercellular interactions

Mukherjee

Nguyen

et al. 2023

Preprint

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Background: Fibroblasts play a key role in stricture formation in Crohn's disease (CD), but understanding it's pathogenesis requires a systems-level investigation to uncover new treatment targets. We studied full thickness CD tissues to characterize fibroblast heterogeneity and function by generating the first single cell RNA sequencing (scRNAseq) atlas of strictured bowel and providing proof of principle for therapeutic target validation. Methods: We performed scRNAseq of 13 fresh full thickness CD resections containing non-involved, inflamed non-strictured, and strictured segments as well as 7 normal non-CD bowel segments. Each segment was separated into mucosa/submucosa or muscularis propria and analyzed separately for a total of 138 tissue samples and 409,001 cells. We validated Cadherin-11 (CDH11) as a potential therapeutic target by using whole tissues, isolated intestinal cells, NanoString nCounter, next generation sequencing, proteomics and animal models. Results: Our integrated dataset revealed fibroblast heterogeneity in strictured CD with the majority of stricture selective changes detected in the mucosa/submucosa, but not the muscle layer. Cell-cell interaction modeling revealed CXCL14+ as well as MMP/WNT5A+ fibroblasts displaying a central signaling role in CD strictures. CDH11, a fibroblast cell-cell adhesion molecule, was broadly expressed and upregulated, and its pro-fibrotic function was validated by NanoString nCounter, RNA sequencing, tissue target expression, in vitro gain- and loss-of-function experiments, proteomics, and two animal models of experimental colitis. Conclusion: A full-thickness bowel scRNAseq atlas revealed previously unrecognized fibroblast heterogeneity and interactions in CD strictures and CDH11 was validated as a potential therapeutic target. These results provide a new resource for a better understanding of CD stricture formation and opens potential therapeutic developments.

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Cytomegalovirus Infection Exacerbates Experimental Colitis by Promoting IL-23 Production

Cited by 8 publications

References 31 publications

Acute cytomegalovirus infection modulates the intestinal microbiota and targets intestinal epithelial cells

Acute cytomegalovirus infection modulates the intestinal microbiota and targets intestinal epithelial cells

Acute Cytomegalovirus Infection Modulates the Intestinal Microbiota and Targets Intestinal Epithelial Cells

Stricturing Crohn’s disease single-cell RNA sequencing reveals fibroblast heterogeneity and intercellular interactions

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