Tailoring modifications of polysaccharides in Mycobacterium tuberculosis

摘要 原核细胞包膜聚糖，即脂多糖（LPS）和 具有离散取代基如糖、氨基酸、磷酸酯或酰基的（脂）磷壁酸是一种脂族磷壁酸。 革兰氏阴性和革兰氏阳性细菌用来调节其细胞表面的众所周知的策略 特性，它们与环境相互作用的方式，它们对杀生物剂和宿主防御的抗性，以及 致病性虽然有证据表明，结核分枝杆菌（Mtb）类似地装饰其主要 细胞包膜聚糖，阿拉伯半乳聚糖（AG）和脂阿拉伯甘露聚糖（LAM），具有各种定制取代基， 人们对其生物学意义知之甚少。我们实验室发现的生物合成机制 负责合成并将这些离散的基序转移到AG和LAM，并产生 第一个在其生物合成中有缺陷的Mtb敲除突变体为旨在 了解这些基序在Mtb的生理学和免疫发病机制中的功能。我们 假设Mtb已经进化到用一系列不同的 策略性地放置取代基以促进其在宿主环境中的存活。因此 多学科研究团队，在分枝杆菌细胞包膜遗传学方面具有互补的专业知识 和糖生物学，结核病免疫发病机制，和碳水化合物化学在这里提出调查如何 简单（氨基/硫代）糖或其他带电基团策略性地放置在Mtb细胞包膜内 不仅影响该微生物的生理学（目的1），而且影响肺部感染的过程， 感染C3 HeB/FeJ小鼠的先天性和适应性免疫的病理学和发展（目的2），以及 Mtb与宿主巨噬细胞和树突状细胞的相互作用，从而促进宿主内的存活（Aim 3）。最终，这些研究有望导致有关生物学意义的重要新知识 分支杆菌独特细胞壁的未充分研究的方面。

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.