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Peptidoglycan Assembly, Degradation, and Function in Pathogenic Chlamydia

致病性衣原体中肽聚糖的组装、降解和功能

基本信息

批准号：
10062849
负责人：
Anthony T Maurelli
金额：
$ 38.13万
依托单位：
UNIVERSITY OF FLORIDA
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：
2016-12-05 至 2022-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10062849
关键词：
Alleles Animals Antibiotics Architecture Area Bacteria Bacterial Infections Bacterial Sexually Transmitted Diseases Biochemical Biological Assay Biology Blindness Cell Shape Cell Wall Cell division Cells Cellular Morphology Chlamydia Chlamydia Infections Chlamydia genome Chlamydia trachomatis Complement Conflict (Psychology)Development Disease Enzymes Fluorescence Microscopy Gene Expression Genes Genetic Genetic Transformation Genital Genitalia Goals Gram-Negative Bacteria Growth Human Immune Immune response Immune system Inflammation Inflammatory Response Innate Immune Response Innate Immune System Knock-out Knowledge Label Life Cycle Stages Lung Maintenance Mass Spectrum Analysis Metabolic Methods Microbe Microscopy Modification Molecular Mutagenesis Osmotic Pressure Pathogenicity Pathologic Processes Pathway interactions Pelvic Inflammatory Disease Peptidoglycan Phase Physiology Play Polysaccharides Population Predisposition Prevention Process Production Recycling Regulation Reporter Reporting Reproductive Health Research Research Personnel Resolution Role Signaling Molecule Stress Structure Suggestion Techniques Technology Testing Thinness Tissues Translating Woman antimicrobial enzyme biosynthesis extracellular fluorescence imaging host-microbe interactions insight member novel therapeutics pathogenic bacteria periplasm polymerization promoter protein complex public health relevance receptor response trait vector

项目摘要

ABSTRACT Chlamydiae are obligate intracellular bacterial pathogens that cause disease in human and animal populations worldwide. C. trachomatis is the most prominent cause of both bacterial sexually transmitted disease and infectious blindness in the world. Peptidoglycan (PG) plays a critical role in the physiology of all bacteria. It determines cell morphology, provides protection against osmotic stress, and plays a critical role in cell division. Fragments of PG are also recognized by mammalian receptors and stimulate the host inflammatory response during bacterial infection. Although recent metabolic labeling techniques finally succeeded in demonstrating the presence of PG in Chlamydia, large gaps in our knowledge still remain. What role does PG play in cell division? How are PG glycan chains assembled in the chlamydial periplasm? How does Chlamydia limit the production of degradation fragments that can stimulate the innate immune response? Chlamydia infection in both the ocular as well as genital niches induces a severe inflammatory response that leads to tissue damage including blindness and pelvic inflammatory disease. It is unclear to what extent components of Chlamydia PG are responsible for this response. We need more insight into how Chlamydia synthesizes and degrades its peptidoglycan to better understand the pathologic processes of Chlamydia disease. The long-term goal is to determine the functions of peptidoglycan in Chlamydia physiology, specifically in cell division and development. The central hypothesis to be tested is that the PG synthesized by Chlamydia plays critical roles in cell division and the host immune response. A major focus will be on PG assembly, degradation, and recycling, which we hypothesize are central to these processes. The interrelated Specific Aims of this proposal are: 1. Elucidate the role played by PG in chlamydial cell division 2. Identify and characterize the genes involved in assembly/polymerization and degradation of chlamydial PG 3. Determine the fate and immunostimulatory potential of chlamydial PG muropeptides subsequent to their degradation Breakthrough technologies in experimental manipulation of Chlamydia make our proposal feasible: genetic transformation of Chlamydia, complementation vectors, inducible promoter constructs for controlled gene expression in Chlamydia, and allelic exchange/knockout mutagenesis. We will also employ metabolic labeling of PG, immune-reporter assays, mass spectroscopy, and superresolution microscopy. This research will fill in critical gaps in our understanding of Chlamydia growth and its recognition by host cells. The knowledge gained will provide information that may translate into new drugs to inhibit chlamydial PG synthesis or disrupt the PG fragments that can trigger the severe inflammation that accompanies Chlamydia infection.

摘要