Bacteria-mucin interactions – Shaping intestinal epithelial responses in health and disease | Bac2MUC | Proyecto | Ficha informativa | H2020 | CORDIS

Descripción del proyecto

Las mucinas intestinales y las respuestas epiteliales a las bacterias

La microbiota del intestino humano está compuesta por los microorganismos del tracto digestivo. Algunos son bacterias comensales beneficiosas, pero otros pueden ser patobiontes que provocan inflamación. La capa de mucosa intestinal define cómo influyen los componentes de la microbiota en la salud y la enfermedad. La capa de mucosa incluye mucinas solubles y mucinas transmembrana epiteliales que regulan las respuestas del huésped. Por el momento, no se conocen en profundidad los mecanismos moleculares de estas interacciones. El proyecto Bac2MUC, financiado con fondos europeos, se propone identificar los mecanismos moleculares que emplean diferentes especies bacterianas para regular las funciones de las mucinas transmembrana en el intestino. Estudios anteriores indicaron que la mucina MUC1 es un receptor clave para la invasión de «Salmonella» en las células epiteliales y la MUC13 es un regulador central de la formación de barreras epiteliales. La hipótesis del proyecto actual es que las interacciones entre las bacterias y las mucinas definen las respuestas epiteliales estimulando la formación de barreras, fomentando la inflamación o mediando en la invasión bacteriana.

Objetivo

The intestinal microbiota consists of beneficial commensal bacteria and pathobionts that cause inflammation. The intestinal mucus layer dictates how specific members of the microbiota affect health and disease. The mucus layer consists of soluble mucins and epithelial transmembrane (TM) mucins that regulate host responses. The molecular mechanisms as to how the intestinal microbiota affect the functions of TM mucins is largely unknown. My recent work shows that TM mucin MUC1 is a key receptor for Salmonella invasion into polarized epithelial cells. We also discovered that MUC13 is a central regulator of epithelial barrier formation. I hypothesize that bacteria-mucin interactions shape epithelial responses by stimulating healthy barrier formation, driving inflammation or mediating bacterial invasion. My aim is to unravel molecular mechanisms via which distinct bacterial species regulate the functions of TM mucins MUC1 and MUC13 in the intestine. The key objectives of Bac2MUC are to: 1. Identify commensal and pathogenic bacteria that target TM mucins 2. Elucidate TM mucin signaling pathways activated by commensal and pathogenic bacteria 3. Determine the function of TM mucins during inflammation and invasion 4. Utilize bacteria-TM mucin interactions to unravel healthy epithelial barrier regulation I will use an innovative large-scale screening platform to identify novel bacteria-mucin interactions. TM mucin signaling pathways during bacterial interaction will be characterized by sortase technology. Cutting-edge technologies such as CRISPR/Cas9 genome editing and advanced microscopy will be applied in established bacterial infection assays with intestinal cell lines and organoids. Bac2MUC is an ambitious and ground-breaking project that will address, for the first time, the complex interplay between intestinal bacteria and TM mucins. This project will contribute to clinical strategies that prevent intestinal inflammation and improve mucosal barrier function.