Role of MARCO in susceptibility and resistance to tuberculosis

描述(申请人提供)：肺结核是由细菌病原体引起的头号死因。在理解结核分枝杆菌如何颠覆巨噬细胞防御功能以持续感染人类宿主方面，存在着根本的差距。长期目标是揭示结核分枝杆菌操纵巨噬细胞介导的宿主防御的机制。这一特殊应用的目的是确定巨噬细胞清道夫受体Marco参与结核分枝杆菌感染的机制，因为Marco基因的单核苷酸多态使宿主对结核病更敏感或更具抗药性。核心假设是MARCO与结核分枝杆菌细胞壁糖脂--海藻糖二乙酸酯--的结合在巨噬细胞对感染的反应中是重要的。这项拟议研究的基本原理是，了解马可如何促进对感染的易感性或抵抗力，将有助于制定干预策略，干扰这一过程。因此，拟议的研究与NIH使命中与发展基础知识相关的部分相关，这可能有助于减轻人类疾病的负担。在强劲的初步数据的指导下，这一假设将通过追求两个具体目标来检验： 具体目标1：确定Marco SNP与结核病易感性相关的机制(S)。 具体目标2：确定Marco SNP与结核病耐药性相关的机制(S)。 在第一个目标下，一种已经被证实的利用Marco缺失构建体的转基因方法将用于测试对TDM包被颗粒和结核分枝杆菌的结合、摄取和下游反应。将使用手头已有的构建和抗体。在第二个目标下，具有或不具有与结核病耐药性相关的单核苷酸多态的人外周血单核细胞将被测试结核分枝杆菌的表达、调节活性和存活率。在拟议的研究完成后，我们期望对Marco如何与TDM和结核分枝杆菌相互作用，以及这种相互作用如何推动对结核病的易感性或耐药性有更好的了解。提出的方法是创新的，因为它关注的是宿主细胞途径，而不是关注抗菌药物的开发，这是现状。这项拟议的研究意义重大，因为它有望为药物治疗提供靶点，这将增强先天免疫系统有效消除结核分枝杆菌感染的能力。 公共卫生相关性：拟议的研究与公共卫生相关，因为Marco-M的基本机制。然后可以利用结核病的相互作用及其后果来操纵感染过程。因此，这些发现有望为开发人类结核病的替代疗法提供新的目标。

DESCRIPTION (provided by applicant): Tuberculosis is the number one cause of death due to a bacterial pathogen. There is a fundamental gap in understanding how Mycobacterium tuberculosis subverts macrophage defense functions in order to persistently infect the human host. The long term goal is to reveal the mechanisms employed by M. tuberculosis bacilli to manipulate macrophage-mediated host defenses. The objective of this particular application is to determine the mechanisms by which the macrophage scavenger receptor MARCO participates in M. tuberculosis infection, since single nucleotide polymorphisms in the MARCO gene render the host more susceptible or resistant to tuberculosis. The central hypothesis is that binding of MARCO by the M. tuberculosis cell wall glycolipid, trehalose dimycolate, is important in the macrophage response to infection. The rationale for the proposed research is that understanding how MARCO drives susceptibility or resistance to infection will enable intervention strategies to be developed that will interfere with this process. Thus, the proposed research is relevant to that part of NIH's mission that pertains to developing fundamental knowledge that will potentially help to reduce the burdens of human disease. Guided by strong preliminary data, this hypothesis will be tested by pursuing two specific aims: Specific Aim 1: Determine the mechanism(s) for the MARCO SNP associated with susceptibility to TB. Specific Aim 2: Determine the mechanism(s) for the MARCO SNP associated with resistance to TB. Under the first aim, an already proven transfection approach, using MARCO deletion constructs, will be used to test binding, uptake, and downstream responses to TDM-coated particles and M. tuberculosis. Constructs and antibodies that are already on hand will be used. Under the second aim, human peripheral blood monocytes with or without the single nucleotide polymorphism associated with resistance to tuberculosis will be tested for expression, regulatory activity, and survival of M. tuberculosis. Upon completion of the proposed study, we expect to have a better understanding of how MARCO interacts with TDM and M. tuberculosis and how this interaction drives either susceptibility or resistance to tuberculosis. The proposed approach is innovative, because it focuses on a host cell pathway rather than focusing on the development of antibacterial drugs, which is the status quo. The proposed research is significant because it is expected to offer targets for drug therapies, which will enhance the ability of the innate immune system to effectively eliminate M. tuberculosis infection. PUBLIC HEALTH RELEVANCE: The proposed research has relevance to public health because the fundamental mechanisms of the MARCO-M. tuberculosis interaction and its consequences can then be used to manipulate the course of infection. Thus, the findings are expected to provide new targets for developing alternative therapies for tuberculosis in human beings.