YopM and protective innate defenses against plague

YopM 和针对鼠疫的保护性先天防御

• 批准号: 8017377
• 负责人: SUSAN C STRALEY
• 金额: $ 47.13万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-03-16 至 2013-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8017377
• 关键词: Biology; Bubonic Plague; CD8B1 gene; Cells; Cytokine Signaling; Cytotoxic T-Lymphocytes; Data; Dendritic Cells; Down-Regulation; Effector Cell; Exposure to; Foundations; Human; Immune; Immune response; Infection; Interleukin-1; Interleukin-12; Interleukin-15; Interleukin-18; Knockout Mice; Lung; Maps; Mediating; Messenger RNA; Mus; Natural Killer Cells; Parents; Pathway interactions; Plague; Pneumonic Plague; Population; Predictive Value; Reporting; Resistance; Signal Pathway; Signal Transduction; Spleen; T-Lymphocyte; Testing; Therapeutic Intervention; Time; Toxin; Virulence; Virulent; Yersinia pestis; cDNA Arrays; chemokine; cytokine; insight; mRNA Expression; macrophage; microbial host; mouse model; mutant; neutrophil; pathogen; prevent; research study

DESCRIPTION (provided by applicant): Yersinia pestis, the causative agent of plague, delivers a set of 6 Yop toxins that act within host cells to negate and modulate signaling pathways that orchestrate host innate defenses that are crucial for developing an effective immune response. This proposal focuses on the mechanism of YopM. We have found that YopM specifically causes a global loss of natural killer cells, and those NK cells remaining do not contain detectable mRNA for IFNg. Concomitantly, YopM causes down-regulation in macrophages of net mRNA expression for key proinflammatory cytokines. In this project, we will test the hypothesis that YopM acts directly on cells such as macrophages and dendritic cells to prevent expression of cytokines such as IL- 15 and IL-12 that synergize to activate effector cells such as macrophages, polymorphonuclear neutrophils, natural killer cells, and cytolytic T cells for controlling numbers of Y. pestis. In Aim 1, we will determine whether YopM's action is mediated by hypothesized key cells by comparing the infection dynamics for virulent and YopM- Y. pestis (viable numbers, dissemination as a function of time) and host response (cell populations and cytokines) in primary pneumonic plague and bubonic plague in mice ablated for the cells genetically or by manipulation. In Aim 2, we will test our hypothesis that the Th1 cytokine and chemokine pathway mediates different host responses to YopM+ and YopM- Y. pestis between d 1 and d 3 to 4 p.i. in bubonic and pneumonic plague by infecting knockout mice or mice ablated for hypothesized key cytokines and analyzing the resulting infection dynamics and host response. In Aim 3, we will map the signaling circuitry of YopM's pathogenic effects by comparing transcriptional profiles (cDNA microarrays) and analyses of intracellular cytokines in purified macrophages from mice with pneumonic or bubonic plague due to virulent and YopM- Y. pestis. The data will reveal the pathogenic mechanism of YopM by identifying cells, cytokines, and signaling pathways modulated by YopM during plague. The findings will provide a completely new understanding of the biology of plague from both microbial and host perspectives as well as provide a framework for rational enhancement of resistance to plague in people threatened with exposure to plague. The data will reveal immune deviation points during plague and could identify potential therapeutic intervention targets. The findings also will provide a better understanding of mammalian innate defenses and insight into evasive mechanisms of pathogens and will facilitate the defeat of important human pathogens that are not select agents.

描述（由申请人提供）：鼠疫的致病药物耶尔西尼亚·佩斯蒂斯（Yersinia Pestis）提供了一组6 YOP毒素，这些毒素在宿主细胞内作用，以消除和调节信号传导途径，这些信号通路协调宿主先天防御，这对于开发有效的免疫反应至关重要。该提案着重于YOPM的机制。我们发现YOPM专门引起天然杀伤细胞的全球损失，而这些NK细胞仍不包含IFNG的可检测mRNA。同时，YOPM引起关键促炎细胞因子净mRNA表达巨噬细胞的下调。在该项目中，我们将检验以下假设：YOPM直接作用于巨噬细胞和树突状细胞等细胞，以防止细胞因子的表达，例如IL-15和IL-12，它们协同激活巨噬细胞，例如巨噬细胞，例如多形性中性粒细胞中性粒细胞，天然杀伤细胞和细胞质细胞的T细胞，用于控制Y。在AIM 1中，我们将通过比较YOPM的作用是通过假设的关键细胞介导的，通过比较毒性和Yopm-Y.鼠疫的感染动态（可行数量，传播作为时间的函数）和宿主反应（细胞种群和细胞因子和细胞因子）（细胞种群和细胞因子）在原发性肺炎和Bubonic plague中的细胞中或bubonic plag的细胞中被吸收或bubonic plag。在AIM 2中，我们将检验我们的假设，即Th1细胞因子和趋化因子途径介导了对Yopm+和Yopm-Y. pestis的不同宿主反应在d 1至d 3至4 p.i之间。通过感染基因敲除小鼠或小鼠消融用于假设的关键细胞因子并分析所得的感染动力学和宿主反应的小鼠，通过感染敲除小鼠或肺炎鼠疫。在AIM 3中，我们将通过比较转录曲线（cDNA微阵列）（cDNA微阵列）和肺内细胞因子的分析来绘制YOPM的致病作用的信号传导回路，并分析因肺炎或bubonic鼠的纯化巨噬细胞中纯化的巨噬细胞中因肺炎或bub鼠而引起的pest虫。数据将通过识别鼠疫期间YOPM调节的细胞，细胞因子和信号通路来揭示YOPM的致病机制。这些发现将从微生物和宿主的角度从微生物和宿主角度提供对瘟疫生物的全新理解，并为理性增强对鼠疫的瘟疫的抵抗力增强的框架。数据将揭示鼠疫期间的免疫偏差点，并可以识别潜在的治疗干预靶标。这些发现还将更好地理解哺乳动物的先天防御和对病原体的回避机制的见解，并促进失败不是精选药物的重要人类病原体。

项目成果

YopM and plague.

YopM 和瘟疫。

• DOI: 10.1007/978-1-4614-3561-7_31
• 发表时间: 2012
• 期刊: Advances in experimental medicine and biology
• 作者: Straley,SusanC

Toward a molecular pathogenic pathway for Yersinia pestis YopM.

• DOI: 10.3389/fcimb.2012.00155
• 发表时间: 2012
• 期刊: Frontiers in cellular and infection microbiology
• 影响因子: 5.7
• 作者: Uittenbogaard AM;Chelvarajan RL;Myers-Morales T;Gorman AA;Brickey WJ;Ye Z;Kaplan AM;Cohen DA;Ting JP;Straley SC
• 通讯作者: Straley SC