Role of MARCO in susceptibility and resistance to tuberculosis

描述（由申请人提供）：结核病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破坏巨噬细胞防御功能以持续感染人类宿主方面存在根本性的差距。长期目标是揭示M.结核杆菌操纵巨噬细胞介导的宿主防御。本申请的目的是确定巨噬细胞清道夫受体MARCO参与M.在某些情况下，由于MARCO基因中的单核苷酸多态性使宿主对结核病更敏感或更耐药，因此可以预防结核病感染。中心假设是M.结核细胞壁糖脂海藻糖二霉菌酸酯在巨噬细胞对感染的反应中是重要的。拟议研究的基本原理是，了解MARCO如何驱动对感染的易感性或抵抗力，将使干预策略能够干预这一过程。因此，拟议中的研究与NIH的使命的一部分有关，该使命涉及开发可能有助于减轻人类疾病负担的基础知识。在强有力的初步数据的指导下，将通过追求两个具体目标来检验这一假设： 具体目标1：确定与TB易感性相关的MARCO SNP的机制。 具体目标2：确定MARCO SNP与TB耐药性相关的机制。 在第一个目标下，使用MARCO缺失构建体的已经证明的转染方法将用于测试对TDM包被的颗粒和M的结合、摄取和下游响应。结核将使用现有的构建体和抗体。在第二个目标下，将检测具有或不具有与结核病抗性相关的单核苷酸多态性的人外周血单核细胞的M的表达、调节活性和存活。结核在拟议的研究完成后，我们希望有一个更好的了解如何MARCO与TDM和M。以及这种相互作用如何驱动对结核病的易感性或耐药性。所提出的方法是创新的，因为它专注于宿主细胞途径，而不是专注于抗菌药物的开发，这是现状。这项研究意义重大，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M的能力。肺结核感染。 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。结核病的相互作用及其后果可以用来操纵感染过程。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靶点。

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.