Tailoring modifications of polysaccharides in Mycobacterium tuberculosis

摘要 原核细胞被膜多聚糖的共价修饰，即脂多糖和 磷壁酸，具有糖、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，它们对杀生剂和宿主防御的抵抗力，以及 致病性。尽管有证据表明结核分枝杆菌(Mtb)类似地修饰了它的主要 细胞被膜多聚糖，阿拉伯半乳聚糖(AG)和脂阿拉伯甘露聚糖(LAM)，具有各种剪裁取代基， 人们对它们的生物学意义知之甚少。我们实验室发现的生物合成机器 负责将这些离散的基序合成并转移到AG和LAM，并生成 首先，缺乏生物合成的结核分枝杆菌基因敲除突变体为研究开辟了道路 了解这些基序在结核分枝杆菌的生理和免疫发病机制中的作用。我们 假设结核分枝杆菌已经进化到用一组不同的 战略性地放置取代基，以促进其在宿主环境中的生存。因此，a 在分枝杆菌细胞膜遗传学方面具有互补专业知识的多学科研究团队 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了研究如何 简单(氨基/硫代)糖或其他带电基团战略性地放置在MTB细胞包膜环境中 不仅影响这种微生物的生理(目标1)，而且还影响肺部感染的过程， C3HeB/FEJ感染小鼠先天免疫和获得性免疫的病理和发展(目标2)，以及 结核分枝杆菌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(目的 3)。最终，这些研究有望带来有关生物意义的重大新知识。 分枝杆菌独特细胞壁的未被充分研究的方面。

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.