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Tailoring modifications of polysaccharides in Mycobacterium tuberculosis

结核分枝杆菌多糖的剪裁修饰

基本信息

批准号：
10387219
负责人：
Mercedes Gonzalez-Juarrero
金额：
$ 51.17万
依托单位：
COLORADO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-17 至 2026-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10387219
关键词：
Academia Address Affect Amino Acids Amino Sugars Anabolism Attention Bacillus Biochemical Biochemistry Biocide Biological Biological Markers C3HeB/FeJ Mouse COVID-19 Carbohydrate Chemistry Carbohydrates Cause of Death Cell Wall Cell surface Cells Charge Colorado Dendritic Cells Development Ensure Environment Galactosamine Generations Genetic Genus Mycobacterium Glycobiology Gram-Positive Bacteria Granuloma Host Defense Infection Infectious Agent Institutes Knock-out Knowledge Laboratories Lead Lipopolysaccharides Lung infections Mediating Membrane Modeling Modification Mus Mycobacterium Infections Mycobacterium tuberculosis Natural Immunity Necrosis Pathogenesis Pathogenicity Pathology Patients Physiological Physiological Processes Physiology Play Polysaccharides Prokaryotic Cells Research Personnel Resistance Role Stress Structure Surface Properties Taiwan Testing Therapeutic Universities Virulence Wheat acyl group adaptive immunity arabinogalactan cell envelope design environmental stressor immunopathology innovation inorganic phosphate lipoarabinomannan lipomannan lipoteichoic acid macrophage microorganism multidisciplinary mutant mycobacterial pathogen physical property prophylactic response sugar thiosugar transcriptomics

项目摘要

Abstract The covalent modification of prokaryotic cell envelope glycans, namely lipopolysaccharide (LPS) and (lipo)teichoic acids, with discrete substituents such as sugars, amino acids, phosphates or acyl groups, is a well-known strategy used by Gram-negative and Gram-positive bacteria to modulate their cell surface properties, the way they interact with their environment, their resistance to biocides and host defenses, and pathogenicity. Although evidence exists that Mycobacterium tuberculosis (Mtb) similarly decorates its major cell envelope glycans, arabinogalactan (AG) and lipoarabinomannan (LAM), with various tailoring substituents, little is known of their biological significance. The discovery by our laboratories of the biosynthetic machineries responsible for the synthesis and transfer of these discrete motifs to AG and LAM, and the generation of the first Mtb knock-out mutants deficient in their biosynthesis have opened the way to studies aimed at understanding the function of these motifs in the physiology and immunopathogenesis of Mtb. We hypothesize that Mtb has evolved to modify its cell-envelope glycans with a distinct array of strategically placed substituents to promote its survival in the host environment. Accordingly, a multidisciplinary team of investigators with complementary expertise in mycobacterial cell envelope genetics and glycobiology, TB immunopathogenesis, and carbohydrate chemistry here proposes to investigate how simple (amino/thio)sugars or other charged groups strategically placed within the Mtb cell envelope landscape affect not only the physiology of this microorganism (Aim 1), but also the course of pulmonary infection, pathology and development of innate and adaptive immunity in infected C3HeB/FeJ mice (Aim 2), and the interactions of Mtb with host macrophages and dendritic cells thereby promoting survival within the host (Aim 3). Ultimately, these studies are expected to lead to significant new knowledge about the biological significance of understudied aspects of the unique cell wall of mycobacteria.

摘要