Surface Proteins of Bacillus anthracis

炭疽杆菌表面蛋白

基本信息

批准号：
10682088
负责人：
Dominique M. Missiakas
金额：
$ 40.13万
依托单位：
UNIVERSITY OF CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-01-01 至 2027-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10682088
关键词：
Adhesions Affect Alveolar Macrophages Animals Anthrax disease Anti-Bacterial Agents Attenuated Vaccines Bacillus Bacillus anthracis Bacillus anthracis spore Bacillus cereus Bacteria Bacterial Adhesins Binding Biochemical Candidate Disease Gene Carbohydrates Cavia Cell Communication Cell Cycle Cell Wall Cell membrane Cells Collection Communicable Diseases Complex Consumption Cultured Cells Cutaneous Data Dendritic Cells Disease Edema Enabling Factors Environment Enzymes Epithelium Food Contamination Gastrointestinal tract structure Genes Germination Goals Gram-Positive Bacteria Growth Host Defense Human Hydrolase Immunocompetent Infection Infectious Diseases Research Ingestion Inhalation Insecta Integrins Intercellular Junctions Intestinal Mucosa Intestines Invaded Kinetics Length Libraries Life Style Ligation Link Lung Lymphatic System Lymphoid Tissue M cell Mammals Mediating Membrane Proteins Modeling Molecular Mucins Mus Mutation Organism Organoids Pathogenesis Pathway interactions Penetration Peptidoglycan Pharmaceutical Preparations Physically Challenged Plasmids Polymerase Polymers Polysaccharides Process Proteins Reproduction spores Research Resistance Route Shapes Site Structure Surface Testing Thick Transferase Virulence Virulent Viscosity base bioweapon cell growth gastrointestinal gastrointestinal infection glycosyltransferase guinea pig model intestinal epithelium knockout animal lethal factor member monocyte monolayer mucinase mutant novel pathogen respiratory transcytosis uptake

项目摘要

ABSTRACT Bacillus anthracis, the anthrax agent, is a member of the Bacillus cereus sensu lato group, which includes invasive pathogens of mammals or insects as well as nonpathogenic environmental strains. Clade 1 members of the B. cereus s.l. group can exchange virulence-plasmids via horizontal transfer with B. anthracis to cause anthrax-like disease too. The natural route of infection is ingestion, often by grazing animals or, in humans, by the consumption of spore-contaminated food (gastrointestinal, GI anthrax). The proposal aims to determine the mechanisms of B. anthracis spore invasion across intestinal epithelia. The central hypothesis is that spores of B. anthracis and anthrax-causing strains germinate in the intestinal tract of infected animals. Our working model postulates that vegetative bacilli secrete several enzymes with mucin-binding and mucin-degrading activities to penetrate the thick mucin layer. Next, the adhesins BslA and BslB mediate uptake of B. anthracis into intestinal cells. BslA and BslB are two of 22 S-layer associated proteins (BSLs) that form the surface (S)- protein layer. BSLs associate via S-layer homology (SLH)-domains with secondary cell wall polysaccharide (SCWP), a peptidoglycan linked carbohydrate polymer. The integrity of the S-layer and SCWP is important for the activity of BSLs. Further, the bslA gene is located on the mobilizable pXO1 virulence plasmid. Thus, we propose that surface-protein layers contribute broadly to the pathogenesis of anthrax-causing organisms. Here, we will use mice and intestinal organoids to model GI anthrax and test our predictions. We propose to study the pathway for the synthesis of SCWP that is required to display the surface-protein layer and is essential for growth. We expect that the elucidation of the assembly pathway of SCWP will serve as a paradigm for the study of other complex polymers of Gram-positive bacteria and reveal new targets of antibacterial drugs. We anticipate that unravelling intestinal mucosa interactions with anthrax and anthrax-like pathogens will collectively advance the field of infectious diseases research.

抽象的炭疽芽孢杆菌（Bacillus anthracis）是炭疽病原，是蜡状芽孢杆菌（Bacillus cereus sensu lato）的成员，其中包括哺乳动物或昆虫的侵入性病原体以及非致病性环境菌株。分支 1 成员 B. cereus s.l. 的群体可以通过水平转移与炭疽芽孢杆菌交换毒力质粒，从而引起还有类似炭疽病的疾病。感染的自然途径是摄入，通常是通过放牧动物或人类摄入食用受孢子污染的食物（胃肠道、胃肠道炭疽）。该提案旨在确定炭疽芽孢杆菌孢子侵入肠上皮的机制。中心假设是孢子炭疽芽孢杆菌和引起炭疽病的菌株在受感染动物的肠道中发芽。我们的工作模型假设营养杆菌分泌多种具有粘蛋白结合和粘蛋白降解作用的酶活动穿透厚厚的粘蛋白层。接下来，粘附素 BslA 和 BslB 介导炭疽芽孢杆菌的摄取进入肠细胞。 BslA 和 BslB 是形成表面 (S) 的 22 个 S 层相关蛋白 (BSL) 中的两个 - 蛋白质层。 BSL 通过 S 层同源 (SLH) 结构域与次生细胞壁多糖结合 (SCWP)，一种肽聚糖连接的碳水化合物聚合物。 S 层和 SCWP 的完整性对于 BSL 的活动。此外，bslA基因位于可移动的pXO1毒力质粒上。因此，我们提出表面蛋白层对引起炭疽生物体的发病机制有广泛贡献。这里，我们将使用小鼠和肠道类器官来模拟胃肠道炭疽并测试我们的预测。我们建议学习 SCWP 的合成途径，是展示表面蛋白层所需的，并且对于生长。我们期望 SCWP 组装途径的阐明将成为研究革兰氏阳性菌的其他复杂聚合物并揭示抗菌药物的新靶点。我们预计解开肠粘膜与炭疽和炭疽样病原体的相互作用将共同推进传染病研究领域。