Surface Proteins and Sortases of Bacillus anthracis

炭疽杆菌的表面蛋白和分选酶

• 批准号: 7334725
• 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/7334725
• 关键词: Address; Animal Model; Animals; Anthrax disease; Apoptosis; Bacillus (bacterium); Bacillus anthracis; Bacillus anthracis spore; Biochemical Genetics; Biochemistry; Biological Phenomena; Blood; Brain; Cell Wall; Cells; Condition; Cytolysis; Cytoplasm; Deposition; Development; Disease; Edema; Endothelial Cells; Epithelium; Event; Future; Genes; 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病的病原体， 动物宿主，并将微生物发育与疾病发病机制联系起来。后病原体 宿主上皮细胞的交叉和巨噬细胞的吞噬，孢子的萌发和 营养细胞存在于吞噬体内。杆菌随后逃离吞噬体膜 并在巨噬细胞的细胞质中复制感染的巨噬细胞最终溶解， 然后杆菌在所有组织中细胞外繁殖，包括血液、肝、脾、肺、脑和 肠B的γ-D-聚谷氨酸胶囊。炭疽病提供了对吞噬细胞的抵抗力， 杀人水肿毒素和致死毒素的分泌诱导免疫细胞凋亡， 内皮组织这些事件介导宿主杀死，随后是孢子形成， 环境传播和向新宿主的传播。本提案探讨了以下方面的作用： 炭疽致病过程中的分选酶和锚定表面蛋白（i）孢子 进入，（ii）营养杆菌侵入巨噬细胞或宿主组织，（iii）细胞外复制 （iv）死亡宿主的孢子形成。两个分选酶基因在大肠杆菌中表达。 营养杆菌和铁饥饿条件下（srtA和srtB），如发生在宿主组织。一 第三分选酶基因（srtQ）仅在孢子形成期间表达。每个分选酶识别 特异性分选信号并将表面蛋白质底物锚定在细菌包膜中，从而 为B的感染性生命周期提供独特的特性。炭疽病分选酶C锚定的BasH 和Basl沉积在孢子肽聚糖中。孢子被膜的一种新机制 由于srtC对于宿主中感染性孢子的形成是必需的， 组织中分选酶B锚定的BasK是血红素铁清除所必需的，而分选酶A 锚定的BasC和内化蛋白样BasJ参与巨噬细胞复制。使用B。炭疽 Sterne和艾姆斯菌株进行遗传和生化分析， 表面蛋白和分选酶在炭疽病发病机制中作用将得到解决。B。炭疽是一种 重要生物恐怖威胁剂，这项研究建议将提供未来的治疗和 通过揭示炭疽病发病机理的潜在生物学现象进行预防性干预。