Yersina perstis interactions with macrophages

持久耶尔森氏菌与巨噬细胞的相互作用

• 批准号: 11007413
• 负责人: Catherine Ayn Brissette
• 金额: $ 22.57万
• 依托单位: UNIVERSITY OF NORTH DAKOTA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/11007413
• 关键词: Yersina; perstis; interactions; macrophages

Plague, an emerging infectious disease endemic to multiple continents, including North and South America, is a top priority in national biodefense. Studying pathogenic yersiniae, the bacteria responsible for plague, provides valuable insights into pathogenesis and evolution. Genomic sequencing of the Yersinia genus and extensive Yersinia pestis genomes spanning from the Bronze Age to the present offer a rich resource for this research. A distinct feature of plague infections is the lack of inflammation at bacterial replication sites. Recent studies on pneumonic plague reveal a two-phase course: a delayed inflammatory response followed by a highly inflammatory phase as the disease progresses. In the initial phase, non-human primate and mouse models show no cellular infiltration. Extracellular presence of Y. pestis in primate lungs does not trigger inflammation. In a rat model of bubonic plague, neutrophil infiltration into draining lymph nodes is delayed, and infected sites undergo necrosis instead of inflammation. Comparisons between Y. pseudotuberculosis and Y. pestis infections demonstrate neutrophil recruitment but inadequate containment of the infection. Research on the type III secretion system and other virulence factors has explored their role in neutralizing early inflammatory responses. However, understanding macrophage polarization during early plague stages remains incomplete. A central hypothesis suggests that Y. pestis prevents inflammation by inhibiting M1 polarization or inducing M2 macrophages Investigating these mechanisms will enhance knowledge of how macrophage polarization contributes to early immune suppression in plague, preventing the infiltration of polymorphonuclear leukocytes (PMNs) and promoting the initial anti-inflammatory stage of plague. Aim 1. Investigate macrophage polarization after Yersinia pestis exposure to block inflammation by either inhibiting M1 polarization or inducing M2 macrophages. Aim 2. Determine signaling pathways induced and mechanisms used by Y. pestis to influence macrophage polarization. Aim 3. Examine the virulence factors utilized by Y. pestis to polarize macrophages.

鼠疫是一种新出现的传染病，流行于多个大陆，包括北方 和南美洲，是国家生物防御的重中之重。研究致病性耶尔森菌， 造成鼠疫的细菌，为发病机制和进化提供了宝贵的见解。 耶尔森氏菌属和广泛的鼠疫耶尔森氏菌基因组的基因组测序 从青铜时代到现在，为这项研究提供了丰富的资源。 鼠疫感染的一个显着特征是细菌复制时缺乏炎症 网站。最近对肺鼠疫的研究揭示了一个两阶段的过程：迟发性炎症 随着疾病的进展，反应随之而来的是高度炎症阶段。在最初的 阶段，非人灵长类动物和小鼠模型显示没有细胞浸润。细胞外 灵长类动物肺部存在鼠疫耶尔森氏菌不会引发炎症。在腺鼠疫大鼠模型中 鼠疫，中性粒细胞浸润引流淋巴结被延迟，感染部位经历 坏死而不是炎症。假结核耶尔森氏菌和鼠疫耶尔森氏菌的比较 感染表明中性粒细胞募集，但感染控制不充分。 对III型分泌系统和其他毒力因子的研究探讨了它们在 中和早期炎症反应。然而，了解巨噬细胞极化 在鼠疫早期阶段仍然不完整。一个中心假设表明鼠疫耶尔森氏菌 通过抑制 M1 极化或诱导 M2 巨噬细胞预防炎症 这些机制将增强人们对巨噬细胞极化如何促进早期 鼠疫中的免疫抑制，防止多形核白细胞的浸润 (PMN) 并促进鼠疫的初始抗炎阶段。 目标 1. 研究鼠疫耶尔森氏菌暴露于块后的巨噬细胞极化 通过抑制 M1 极化或诱导 M2 巨噬细胞产生炎症。 目标 2. 确定鼠疫耶尔森氏菌诱导的信号通路和机制 影响巨噬细胞极化。 目标 3. 检查鼠疫耶尔森氏菌用于极化巨噬细胞的毒力因子。