Role of MARCO in susceptibility and resistance to tuberculosis

MARCO 在结核病易感性和耐药性中的作用

• 批准号: 8289054
• 负责人: Kaori Sakamoto
• 金额: $ 40.48万
• 依托单位: UNIVERSITY OF GEORGIA
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-03-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8289054
• 关键词: Affect; Alternative Therapies; Anti-Bacterial Agents; Antibacterial Response; Antibiotic Resistance; Antibodies; Bacillus (bacterium); Bacteriophages; Binding; Binding Sites; Biological Assay; Biology; CD14 gene; Case-Control Studies; Cause of Death; Cell Wall; Cells; Communicable Diseases; Cord Factors; Cysteine; Cytokine Signaling; Data; Development; Gene Structure; Genetic Transcription; Glycolipids; Goals; Hand; Healthcare; Host Defense; Human; Immune response; Immune system; Immunoblotting; In Vitro; Individual; Infection; Inflammatory Response; Inflammatory Response Pathway; Intervention; Introns; Knowledge; Lysosomes; Mediating; Mission; Mycobacterium tuberculosis; Outcome; Pathogenesis; Pathway interactions; Phagosomes; Pharmaceutical Preparations; Pharmacotherapy; Play; Predisposition; Process; Public Health; Publishing; Recording of previous events; Regulation; Reporting; Research; Resistance; Resistance to infection; Role; SR-A proteins; Signal Transduction; Signaling Molecule; Single Nucleotide Polymorphism; Single Nucleotide Polymorphism in Regulatory Sequence; Structure; Testing; Toll-like receptors; Transfection; Trehalose; Tuberculosis; Work; base; cytokine; human disease; immunopathology; improved; innovation; macrophage; macrophage scavenger receptors; microbicide; monocyte; mycobacterial; particle; pathogen; peripheral blood; protein structure; receptor; response; scavenger receptor; transcription factor; uptake

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.

描述（由申请人提供）：结核病是细菌病原体导致的第一大死亡原因。对于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的理解存在根本性的差距。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。这一特定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 基因中的单核苷酸多态性使宿主对结核病更敏感或具有抵抗力。中心假设是 MARCO 与结核分枝杆菌细胞壁糖脂、海藻糖二霉菌酸酯的结合在巨噬细胞对感染的反应中很重要。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有助于制定干预策略来干扰这一过程。因此，拟议的研究与 NIH 使命的一部分相关，即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，该假设将通过追求两个具体目标进行检验： 具体目标 1：确定 MARCO SNP 与结核病易感性相关的机制。 具体目标 2：确定 MARCO SNP 与结核病耐药相关的机制。 第一个目标是，使用 MARCO 缺失构建体的已被证实的转染方法将用于测试 TDM 包被颗粒和结核分枝杆菌的结合、摄取和下游反应。将使用现有的构建体和抗体。在第二个目标下，将测试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表达、调节活性和结核分枝杆菌的存活。完成拟议的研究后，我们希望更好地了解 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驱动结核病的易感性或耐药性。所提出的方法是创新的，因为它关注的是宿主细胞途径，而不是关注现状的抗菌药物的开发。这项研究意义重大，因为它有望为药物治疗提供靶点，从而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。结核病相互作用及其后果可用于控制感染过程。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。

项目成果

Human-Specific Mutations and Positively Selected Sites in MARCO Confer Functional Changes.

MARCO 中的人类特异性突变和积极选择的位点赋予功能变化。

• 发表时间: 2018-02-01
• 影响因子: 10.7
• 作者: Novakowski, Kyle E;Yap, Nicholas V L;Yin, Charles;Sakamoto, Kaori;Heit, Bryan;Golding, G Brian;Bowdish, Dawn M E
• 通讯作者: Bowdish, Dawn M E

Genetic variants of MARCO are associated with susceptibility to pulmonary tuberculosis in a Gambian population.

MARCO 的遗传变异与冈比亚人群对肺结核的易感性有关。

• 发表时间: 2013-04-23
• 作者: Bowdish, Dawn Me;Sakamoto, Kaori;Lack, Nathan A;Hill, Philip C;Sirugo, Giorgio;Newport, Melanie J;Gordon, Siamon;Hill, Adrian Vs;Vannberg, Fredrick O
• 通讯作者: Vannberg, Fredrick O

A naturally occurring transcript variant of MARCO reveals the SRCR domain is critical for function.

MARCO 的天然转录变体揭示了 SRCR 结构域对于功能至关重要。

• 发表时间: 2016-08
• 影响因子: 4
• 作者: Novakowski, Kyle E;Huynh, Angela;Han, SeongJun;Dorrington, Michael G;Yin, Charles;Tu, Zhongyuan;Pelka, Peter;Whyte, Peter;Guarné, Alba;Sakamoto, Kaori;Bowdish, Dawn M E
• 通讯作者: Bowdish, Dawn M E