Tailoring modifications of polysaccharides in Mycobacterium tuberculosis

结核分枝杆菌多糖的剪裁修饰

• 批准号: 10490882
• 负责人: Mercedes Gonzalez-Juarrero
• 金额: $ 63.76万
• 依托单位: COLORADO STATE UNIVERSITY
• 依托单位国家: 美国
• 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/10490882
• 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; Persons; 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

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.

抽象的 核细胞包膜聚糖的共价修饰，即脂多糖（LPS）和 （Lipo）Teichoic Acid，糖，氨基酸，磷酸盐或酰基等离散取代基是一种 革兰氏阴性和革兰氏阳性细菌使用的众所周知的策略来调节其细胞表面 财产，与环境互动的方式，对杀害剂和宿主防御的抵抗以及 致病性。尽管存在有证据表明结核分枝杆菌（MTB）类似地装饰了其专业 细胞包膜，阿拉伯分氏菌（Ag）和脂肪芳族瘤（LAM），带有各种剪裁取代基， 知之甚少，它们的生物学意义。我们的实验室发现生物合成机器的发现 负责将这些离散基​​序的合成和转移到Ag和Lam，以及生成 第一个MTB敲除突变体在其生物合成中缺乏 了解这些基序在MTB的生理学和免疫病变中的功能。我们 假设MTB已进化以修改其细胞 - 内玻璃糖，以不同的阵列 策略性地放置取代基，以促进其在宿主环境中的生存。因此， 多学科研究人员的多学科团队具有分枝杆菌细胞信封遗传学的互补专业知识 这里的糖生物学，结核病免疫发病发生和碳水化合物化学提议研究如何研究 简单的（氨基/硫糖）糖或其他充电基团在MTB细胞包膜景观中策略性地放置 不仅影响这种微生物的生理学（AIM 1），还影响肺部感染的过程， 感染的C3HEB/FEJ小鼠的病理和生育和适应性免疫的病理和自适应免疫（AIM 2）和 MTB与宿主巨噬细胞和树突状细胞的相互作用，从而促进宿主的生存（AIM 3）。最终，这些研究有望导致有关生物学意义的重大新知识 分枝杆菌独特细胞壁的研究不足。