Surface Proteins and Sortases of Bacillus anthracis

炭疽杆菌的表面蛋白和分选酶

• 批准号: 7538357
• 负责人: Olaf Schneewind
• 金额: $ 36.64万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-01-01 至 2011-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7538357
• 关键词: Address; Animal Model; Animals; Anthrax disease; Apoptosis; Bacillus (bacterium); Bacillus anthracis; Bacillus anthracis spore; Biochemical; Biochemistry; Biological Phenomena; Blood; Brain; Cell Wall; Cells; Cytolysis; Cytoplasm; Deposition; Development; Disease; Edema; Endothelial Cells; Epithelium; Event; Future; Genes; Genetic; Germination; Heme Iron; Homologous Gene; Human; Immune; Infection; Integration Host Factors; Intestines; Iron; Life Cycle Stages; Liver; Lung; Mediating; Membrane; Membrane Proteins; Molecular Analysis; Pathogenesis; Peptidoglycan; Phagosomes; Polyglutamic Acid; Preventive Intervention; Property; Reproduction spores; Research Proposals; Resistance; Role; Signal Transduction; Sorting - Cell Movement; Spleen; Staging; Starvation; Structure; Structure of thyroid parafollicular cell; Therapeutic; Tissues; Toxin; anthrax lethal factor; capsule; extracellular; genetic analysis; killings; macrophage; microbial; pathogen; sortase; transmission process

The dormant spores of Bacillus anthracis, the causative agent of anthrax, infect human or animal hosts and tether microbial development to disease pathogenesis. Following pathogen crossing of host epithelia and engulfment by macrophages, spore germination and outgrowth of vegetative cells occurs within phagosomes. Bacilli subsequently escape phagosomal membranes and replicate in the cytoplasm of macrophages. Infected macrophages are eventually lysed, and bacilli then multiply extracellularly in all tissues, including blood, liver, spleen, lungs, brain and intestines. The y-D-polyglutamic acid capsule of B. anthracis provides for resistance to phagocytic killing. Secretion of edema toxin as well as lethal toxin induces apoptosis of immune cells and endothelial tissues. These events mediate host killing, which is followed by spore formation, environmental dissemination and transmission to new hosts. This proposal investigates the role of sortases andanchored surface proteins during the four stages of anthrax pathogenesis - (i) spore entry, (ii) invasion of vegetative bacilli into macrophages or host tissues, (iii) extracellular replication of bacilli, and (iv)spore formation in deceased hosts. Two sortase genes are expressed in vegetative bacilli and under iron starvation conditions (srtA and srtB), as occurs in host tissues. A third sortase gene (srtQ is only expressed during spore formation. Each sortase recognizes specific sorting signals and anchors surface protein substrates in the bacterial envelope, thereby contributing unique properties to the infectious life cycle of B. anthracis. Sortase C anchored BasH and Basl are deposited in spore peptidoglycan. A new and exciting mechanism of spore envelope assembly is described here, as srtC is essential for the formation of infectious spores in host tissues. Sortase B anchored BasK is required for heme-iron scavenging, whereas sortase A anchored BasC and internalin-like BasJ are involved in macrophage replication. Using B. anthracis strains Sterne and Ames for genetic and biochemical analysis, the molecular mechanisms of surface protein and sortase function in anthrax pathogenesis will be addressed. B. anthracis is an important bioterror threat agent and this research proposal will provide future therapeutic and preventive interventions by revealing the underlying biological phenomena of anthrax pathogenesis.

炭疽芽孢杆菌的休眠孢子是炭疽的致病药物，感染了人类或 动物宿主和系绳微生物发育为疾病发病机理。遵循病原体 通过巨噬细胞，孢子发芽和产物的吞噬宿主上皮和吞噬 营养细胞发生在吞噬体中。杆菌随后逃脱吞噬膜 并在巨噬细胞的细胞质中复制。感染的巨噬细胞最终被裂解，并且 然后，杆菌在所有组织中细胞外繁殖，包括血液，肝，脾，肺，大脑和 肠。炭疽芽孢杆菌的Y-D-D-聚谷氨酸囊提供了对吞噬细胞的抗性 杀人。水肿毒素的分泌以及致命的毒素会诱导免疫细胞和 内皮组织。这些事件导致宿主杀戮，其次是孢子形成， 环境传播和向新主机的传播。该提议调查了 排序酶和经结的表面蛋白在炭疽病发病机理的四个阶段 - （i）孢子 进入，（ii）将营养杆菌侵入巨噬细胞或宿主组织，（iii）细胞外复制 在已故宿主中的杆菌和（IV）孢子形成。两个分类基因在 在宿主组织中发生的植物性杆菌以及铁饥饿条件（SRTA和SRTB）。一个 第三排序酶基因（SRTQ仅在孢子形成期间表达。每个排序酶都识别 特定的排序信号和锚定在细菌包膜中的表面蛋白底物，从而 为炭疽芽孢杆菌的传染性生命周期贡献了独特的特性。排序酶C锚定bash BASL沉积在孢子肽聚糖中。孢子信封的一种新的令人兴奋的机制 这里描述了组装，因为SRTC对于宿主中传染性孢子的形成至关重要 组织。血红素铁清除是必需的，而排序酶是锚定的，而排序酶A 锚定的BASC和类似内部素的BASJ参与了巨噬细胞的复制。使用B.炭疽病 斯特恩和AME菌株用于遗传和生化分析，这是分子机制 将解决炭疽发病机理中的表面蛋白质和分子酶功能。 B.炭疽病是 重要的BiotError威胁代理和该研究建议将提供未来的治疗性和 通过揭示炭疽发病机理的潜在生物学现象，进行预防性干预。