Surface Proteins and Sortases of Bacillus anthracis

炭疽病的病原体炭疽芽孢杆菌的休眠孢子会感染人类或 动物宿主和系留微生物的发育与疾病的发病机制有关。追随病原体 寄主上皮细胞与巨噬细胞吞噬、孢子萌发和生长 营养细胞存在于吞噬体内。细菌随后逃离吞噬体膜 并在巨噬细胞的细胞质中复制。被感染的巨噬细胞最终被裂解，并且 然后，细菌在所有组织中进行细胞外繁殖，包括血液、肝脏、脾、肺、脑和 肠子。炭疽杆菌Y-D-聚谷氨酸胶囊具有抗吞噬作用 杀戮。水肿性毒素和致死性毒素的分泌诱导免疫细胞凋亡和 内皮组织。这些事件介导了宿主的杀戮，随后是孢子的形成， 环境传播和传播给新的宿主。这项提案调查了 炭疽病发病四个阶段的分解酶和锚定表面蛋白--(I)孢子 进入，(2)营养细菌侵入巨噬细胞或宿主组织，(3)细胞外复制 (4)死亡寄主的孢子形成。两个排序酶基因在 营养细菌和在缺铁条件下(srtA和srtB)，如在宿主组织中出现的。一个 第三个索酸酶基因(SrtQ)仅在孢子形成过程中表达。每个排序表识别 特定的分选信号并将表面蛋白底物锚定在细菌包膜中，从而 为炭疽杆菌的感染性生命周期贡献了独特的特性。山梨酸酶C锚定Bash 和Basl沉积在孢子肽聚糖中。一种新的激发孢子囊的机制 组装在这里描述，因为srtC是在宿主中形成侵染性孢子所必需的。 纸巾。对于血红素-铁的清除，需要索尔特酶B锚定的遮阳物，而索尔特酶A 锚定的BASC和内源性的BASJ参与巨噬细胞的复制。使用炭疽杆菌 菌株Sterne和Ames用于遗传和生化分析，其分子机制 将讨论炭疽病发病机制中的表面蛋白和分类酶功能。炭疽杆菌是一种 重要的生物恐怖威胁因子和这项研究提案将提供未来的治疗和 通过揭示炭疽病发病的潜在生物学现象进行预防干预。

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.