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Pathogenesis of E. coli and Shigella infections in human enteroid models

人肠模型中大肠杆菌和志贺氏菌感染的发病机制

基本信息

批准号：
10427388
负责人：
MARK DONOWITZ
金额：
$ 203.23万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-07-01 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10427388
关键词：
3-Dimensional Address Anaerobic Bacteria Attention Attenuated Vaccines Biological Response Modifiers Cell Communication Cell model Cell physiology Cells Cellular biology Childhood Clinical Coculture Techniques Collaborations Communicable Diseases Culture Media Dendritic Cells Development Diarrhea Diarrheagenic E. coli Disease Electronic Mail Enteral Enterotoxins Environment Epithelial Escherichia coli Exposure to Functional disorder Funding Gastroenterology Glycoproteins Goals Goblet Cells Human Human Resources Immune Immune Evasion Immune system Immunology International Intestines Laboratories Leukocytes M cell Maryland Measurement Methodology Methods Microbiology Modeling Molecular Mucins Mucous Membrane Organism Pathogenesis Peptide Hydrolases Phagocytes Physiology Production Program Research Project Grants Publications Reagent Recording of previous events Research Research Personnel Research Project Grants Role Serine Protease Shigella Shigella Infections Shigella Vaccines System T-Lymphocyte Telephone Universities Virginia Work antimicrobial peptide base cell motility cytokine diarrheal disease eVisit enteric pathogen enteroaggregative Escherichia coli enterotoxigenic Escherichia coli experience gut inflammation human model improved insight intraepithelial macrophage meetings model development monolayer neutrophil novel pathogen pathogenic bacteria pre-clinical programs response scaffold shear stress tool transcytosis

项目摘要

Pathogenesis of E. coli and Shigella Infections in Human Enteroid Models Overall Description / Summary This first renewal of a funded program Project Grant (PPG) is to continue progress in understanding the pathophysiology and identification of ways to interfere with diarrhea caused by Shigella and two pathotypes of diarrheagenic E. coli (enteroaggregative and enterotoxigenic E. coli). The substantial progress made has resulted from the close collaboration and combined expertise of investigators from the University of Maryland, Johns Hopkins University and the University of Virginia who are using shared models of normal human enteroid and colonoid monolayers exposed to enteric bacterial pathogens as well as human enteroid monolayers co- cultured with innate phagocytic cells present in the intestine. The group of investigators has internationally renowned experience in enteric diseases, as well as in microbiology, gastroenterology, molecular physiology, pediatric infectious diseases, cell biology, molecular pathogenesis, and mucosal immunology. This consortium has interacted and in a superbly collaborative manner sharing technical and scientific information through formal monthly face-to-face or Zoom-based meetings, frequent telephone or electronic communication and visits to laboratories, with the latter being the standard form of interaction of the U Maryland and JHU investigators. The Enteroid and Immunology Cores have developed new tools and methods that were rapidly transferred to the Project investigators, resulting in a significant number of collaborative publications from the PPG. As expected, progress was stepwise with transfer of methodology and reagents for propagating the enteroids, production of monolayers, development of the bacterial-enteroid models, and development of co-cultures with immune cells leading to new insights in the pathogen-enteroid interactions. The overall goal of the PPG remains to increase understanding of the pathophysiology and potential treatments of these three important pathogens. The proposed studies will continue to use normal human enteroids or colonoids, grown on monolayers, and extend this through co-culture to make the model more closely resemble human intestine. This will be accomplished by expanding the co-culture models to a) establish monolayers in a 3D scaffold matrix to facilitate epithelial-immune cell interaction and immune cell movement; b) incorporate macrophages, neutrophils and dendritic cells as well as to develop a new co-culture system that includes intraepithelial γδ +T lymphocytes (IEL); c) apply an enriched M cell model; d) expose the co-culture model to flow-based shear stress as occurs normally in the intestine; e) determine the contribution of an anaerobic environment. As during the past funding period, examination of pathophysiologic aspects common to the diseases studied will serve to integrate the projects. In addition to pathogen specific pathophysiologic aspects, these include the role of mucins, bacterial proteases called SPATES, enterotoxins, secreted cytokines and involvement of co-cultured innate immune cells.

大肠杆菌和志贺氏菌感染在人肠道模型中的发病机制