MIRNA-AIEC

Role of microRNAs in host responses to Crohn's disease-associated adherent-invasive Escherichia coli

 Partecipanti

Mappa

 Word cloud

Esplora la "nuvola delle parole (Word Cloud) per avere un'idea di massima del progetto.

 Obiettivo del progetto (Objective)

'Recent studies have shown dysregulation of microRNAs (miRNAs) in the mucosa of Crohn’s disease (CD) patients, suggesting a role for miRNAs as contributors to inflammatory bowel disease (IBD) susceptibility. The scientists from the host institution previously showed that ileal lesions in CD patients are colonized by pathogenic adherent-invasive Escherichia coli (AIEC), which are able to invade and to replicate within intestinal epithelial cells, and that functional autophagy is required to restrain AIEC replication. The overall hypothesis of this proposal is that miRNA pathway contributes to innate immune responses to AIEC colonization and/or inflammatory activities. The goal of our study is to determine the microRNAs dysregulated in host cells upon infection with AIEC, and the mechanism through which they contribute to responses of the host. In particular, three objectives will be addressed in this project: 1) To determine the potential role and mechanism by which miRNAs modulate the host responses of intestinal epithelial cells (IECs) to AIEC; 2) To investigate the regulation of CEACAM6, a host receptor for AIEC, by miRNAs in IECs during pathophysiological state, and in host responses to AIEC infection; and 3) To test the hypothesis that AIEC impair autophagy to replicate in host cells by modulating expression of host miRNAs. I propose to use IEC culture models of AIEC infection accompanied with bioinformatics tools to identify the miRNAs which are regulators of the key signaling pathways that modulate cross-talk between AIEC and host cells. The proposed studies in this project will shed light on the mechanism by which miRNAs are involved in host responses to AIEC infection, which could help to identify new biomarkers and potential therapeutic targets for IBD.'

Introduzione (Teaser)

European researchers investigated how microbiota could alter the intestine and cellular processes in inflammatory bowel diseases (IBDs). Special attention was given to the role of microRNA (miRNA) regulators as disease biomarkers.

Descrizione progetto (Article)

IBDs such as Crohn's disease (CD) and ulcerative colitis (UC) are believed to emerge from inappropriate inflammatory responses to normal components of the intestinal microbiota. IBD patients present with altered microbiota composition and especially adherent-invasive Escherichia coli (AIEC).

Previous work by the EU-funded 'Role of microRNAs in host responses to Crohn's disease-associated adherent-invasive Escherichia coli' (MIRNA-AIEC) consortium showed that AIEC can invade human intestinal epithelial cells and macrophages, and survive. In addition, AIEC induces pro-inflammatory cytokine production and in mouse models they exacerbate intestinal inflammation.

AIEC control is achieved through a functional mechanism of autophagy, a term used to describe the catabolic processing of dysfunctional cellular components by the cell itself. However, since AIEC prevalence is high in IBD, MIRNA-AIEC scientists presumed it could be due to dysfunctional autophagy.

For this purpose, and based on earlier observations, they sought to identify the factors and mechanisms underlying the control of intracellular AIEC by autophagy. Given that recent evidence shows deregulation of miRNAs in CD patients, project scientists set out to determine the link between miRNAs and IBD susceptibility. The main objectives were to identify which miRNAs become altered upon endothelial cell infection with AIEC and how they induce cellular responses.

The consortium identified 12 miRNAs that were altered in response to AIEC, and interestingly they targeted autophagy-associated genes. Inhibition of these miRNAs restored functional autophagy, and resulted in AIEC clearance as well as reduced inflammation.

Taken together, the results of the study underscore the role of AIEC in autophagy response through altered miRNA expression. They also illustrate that miRNAs are promising therapeutic targets to inhibit the intracellular replication of CD-associated pathogenic bacteria. This information serves as a basis for the future investigation and discovery of new biomarkers and potential therapeutic targets for IBDs.