Identification and Characterization of Pathology Minimization Mechanisms During I

描述(申请人提供)：生物体有两种生存机制：抵抗力和病理最小化。抵抗力是消除病原体的能力，我们对免疫反应是如何启动和执行的有很强的机械性理解。与此相反，我们只知道几种机制，宿主通过这些机制将感染相关的损害降至最低，而不考虑病原体的负载。我的目标是确定和描述宿主将感染相关损害降至最低的机制。我假设宿主诱导病理最小化程序以响应病原体检测和宿主损伤。我将测试和描述对宿主的损害(以急性溶血的形式)是如何在随后的疟原虫感染时使病理最小化的。溶血导致细胞毒性血红素的释放，从而诱导宿主血红素加氧酶-1(HO-1)的表达。当小鼠在结构性低水平或急性溶血后感染疟原虫时，这些小鼠以HO-1依赖的方式表现出对健康的影响减弱。我想更好地描述这种疾病严重性降低的原因。我将通过研究HO-1介导的血红素分解代谢如何最大限度地减少病理来做到这一点。我还将测试干扰素调节因子(IRF)蛋白，一种转录家族 我们已经发现在疟原虫感染时诱导的调节剂，可以调节病理最小化。我们之所以选择关注IRF蛋白，是因为已发表的数据表明，IRF以及IRF调节的基因可以限制不同类型感染引起的病理性数量。这将使用实验室内开发的一种新的分析方法，称为相曲线分析，它允许我们在感染的整个过程中评估微生物对单个宿主的健康影响。这里提出的工作将是第一次系统地识别和表征新的病理最小化机制。该提案还旨在定义这些机制是如何产生的。这些知识可能是理解和开发可诱导的病理最小化机制作为人类经历病原性感染的治疗方法的关键。由于有许多传染病我们无法预防，因此我们能够减少在这些感染期间造成的损害是很重要的。最后，这里提出的工作将作为确定可用于将不可避免的感染的严重性降至最低的机制的模板。

DESCRIPTION (provided by applicant): Organisms have two mechanisms to survive pathogenic infections: resistance and pathology minimization. Resistance is the ability to eliminate pathogens and we have a strong mechanistic understanding of how immune responses are initiated and executed. Contrary to this, we know of only a few mechanisms by which hosts minimize infection-associated damage irrespective of pathogen load. My goal is to identify and characterize mechanisms by which the host minimizes infection-associated damage. I hypothesize that hosts induce pathology minimization programs in response to pathogen detection and host damage. I will test and characterize how damage to the host (in the form of acute hemolysis) mediates pathology minimization upon subsequent Plasmodium infection. Hemolysis leads to the release of cytotoxic heme, which induces expression of host heme oxygenase-1 (HO-1). When mice are infected with plasmodium subsequent to constitutive low-level or acute hemolysis, these mice exhibit a diminished health impact in a HO-1 dependent manner. I would like to better characterize the reason for this diminished disease severity. I will do this by examining how HO-1-mediated heme catabolism minimizes pathology. I will also test whether the Interferon Regulatory Factor (IRF) proteins, a family of transcription regulators we've found to be induced upon Plasmodium infection, can mediate pathology minimization. We have chosen to focus on IRF proteins because published data suggests that IRFs, as well as IRF regulated genes, can limit the amount of pathology incurred in different types of infections. This will be done using a novel analytical method developed within the lab, termed phase curve analysis, which allows us to evaluate the health impact of microbes on individual hosts during the entire course of the infection. The work proposed here will be the first to systematically identify and characterize novel pathology minimization mechanisms. This proposal also aims to define how these mechanisms are induced. This knowledge may be key in understanding and developing inducible pathology minimization mechanisms as therapeutics for humans experiencing pathogenic infections. As there are many infectious diseases we cannot prevent, it is important that we are able to reduce the amount of damage incurred during these infections. Finally, the work proposed here will serve as a template for identifying mechanisms that may be employed to minimize the severity of unavoidable infections.