Modulation of Host Responses by Mycobacterium Tuberculosis

结核分枝杆菌对宿主反应的调节

• 批准号: 8259815
• 负责人: Jyothi Rengarajan
• 金额: $ 43.56万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-01 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8259815
• 关键词: Adaptor Signaling Protein; Antibiotics; Biochemical; Biological Assay; Cell Wall; Cell surface; Cells; Cessation of life; Complement; Complex; Data; Dendritic Cells; Disease Outcome; Drug Delivery Systems; Drug resistance; Environment; Epidemic; Extreme drug resistant tuberculosis; Genetic; Goals; Growth; HIV; Host Defense; Hybrids; Hydrolase; Immune; Immune response; Immunity; Immunosuppression; In Vitro; Infection; Link; Lipoproteins; Lung; Maps; Mediating; Molecular; Monitor; Multi-Drug Resistance; Muramidase; Mus; Mycobacterium smegmatis; Mycobacterium tuberculosis; N-terminal; Names; Natural Immunity; Pathogenesis; Pathology; Pathway interactions; Pattern; Physiological; Production; Proteins; Public Health; Receptor Signaling; Reporter; Research; Resistance; Rest; Role; Serine Hydrolase; Signal Pathway; Signal Transduction Pathway; Site; Source; Specificity; Stress; Surface; System; T cell response; TLR2 gene; TLR4 gene; Testing; Toll-like receptors; Tuberculosis; Virulence; Virulence Factors; adaptive immunity; antimicrobial; base; cell envelope; chemokine; cytokine; extracellular; functional genomics; global health; immune activation; immune resistance; immunoregulation; improved; in vivo; insight; killings; macrophage; microbicide; mouse model; mutant; mycobacterial; novel vaccines; pathogen; public health relevance; receptor; receptor-mediated signaling; response; tuberculosis drugs; tuberculosis treatment

DESCRIPTION (provided by applicant): Tuberculosis (TB) remains a major threat to global public health and infection with Mycobacterium tuberculosis (Mtb) is estimated to result in over 2 million deaths annually. Current TB treatments are long and arduous and contribute to the emergence of multi-drug resistant (MDR)- and extensively drug-resistant (XDR)-TB. In order to develop new vaccines and drugs for TB, we need to understand how Mtb evades innate immunity and survives in hostile immune environments. A central feature of Mtb pathogenesis is its ability to grow within macrophages, modulate their activities and interfere with microbicidal functions. We have identified a cell envelope-localized lipoprotein encoding a serine hydrolase, Rv2224c, which is critical for Mtb virulence in vivo, survival in macrophages and resistance to cell envelope-directed stresses. We have named this protein Hip1 (Hydrolase important for pathogenesis 1). We demonstrate that Hip1 suppresses innate immune responses; hip1 mutants induce enhanced proinflammatory responses downstream of Toll-like receptor (TLR)-signaling in macrophages. We hypothesize that Hip1 modifies cell envelope or secreted substrates to modulate innate immunity and host defense. The focus of this application is to understand how Hip1 suppresses host innate immune pathways and determine the molecular and biochemical mechanisms for Hip1 function. The specific aims are (1) To study the role of Hip1 in suppressing host responses. We will define the TLR-dependent pathways modulated by Hip1 and evaluate whether Hip1-mediated immune suppression promotes Mtb growth in macrophages. We will also determine whether enhanced innate immune responses elicited by the hip1 mutant impact adaptive immunity by studying the priming and functionality of T cell responses. (2) To determine the molecular basis for Hip1 function. First we will characterize the molecular and biochemical basis for Hip1 interaction with a candidate physiological substrate, GroEL2. We will investigate the functional significance of Hip1-dependent cleavage of GroEL2 and its contribution to immune suppression and resisting antimicrobial defense. Second, we will use a panel of synthetic substrates to evaluate the range and specificity of Hip1 hydrolase activity. Finally we will identify additional Hip1 interaction partners and physiological substrates using genetic and biochemical approaches. PUBLIC HEALTH RELEVANCE: The global TB epidemic is fueled by HIV co-infection and the spread of drug resistance, posing a grave threat to public health. The studies outlined here will increase our understanding of an important virulence factor that mediates immune suppression and resistance to host antimicrobial defense. Such proteins are attractive new drug targets for inhibition as they can potentially synergize with antibiotics and simultaneously enhance immune-mediated killing of Mtb.

描述（由申请人提供）：结核病（TB）仍然是全球公共卫生的主要威胁，据估计，结核分枝杆菌（Mtb）感染每年导致超过200万人死亡。目前的结核病治疗是长期和艰巨的，并有助于出现多药耐药（MDR）和广泛耐药（XDR）结核病。为了开发新的结核病疫苗和药物，我们需要了解结核分枝杆菌如何逃避先天免疫并在不利的免疫环境中生存。Mtb发病机制的中心特征是其在巨噬细胞内生长、调节其活性并干扰杀微生物功能的能力。我们已经确定了一个细胞定位的脂蛋白编码的丝氨酸水解酶，Rv 2224 c，这是至关重要的结核分枝杆菌在体内的毒力，在巨噬细胞中的生存和抵抗细胞凋亡定向应力。我们将这种蛋白质命名为Hip 1（Hydrolase important for pathogenesis 1）。我们证明，Hip 1抑制先天性免疫反应; Hip 1突变体诱导增强巨噬细胞Toll样受体（TLR）信号下游的促炎反应。我们推测，Hip 1修改细胞包膜或分泌底物，以调节先天免疫和宿主防御。本申请的重点是了解Hip 1如何抑制宿主先天免疫途径，并确定Hip 1功能的分子和生化机制。具体目的是（1）研究Hip 1在抑制宿主反应中的作用。我们将确定TLR依赖的途径调节Hip 1和评估是否Hip 1介导的免疫抑制促进结核分枝杆菌在巨噬细胞的生长。我们还将通过研究T细胞应答的启动和功能来确定hip 1突变体引起的增强的先天免疫应答是否会影响获得性免疫。(2)确定Hip 1功能的分子基础。首先，我们将表征Hip 1与候选生理底物GroEL 2相互作用的分子和生化基础。我们将研究Hip 1依赖性GroEL 2切割的功能意义及其对免疫抑制和抵抗抗菌防御的贡献。其次，我们将使用一组合成底物来评估Hip 1水解酶活性的范围和特异性。最后，我们将确定额外的Hip 1相互作用的合作伙伴和生理基板使用遗传和生化方法。 公共卫生相关性：艾滋病病毒合并感染和耐药性的传播助长了全球结核病的流行，对公共卫生构成严重威胁。这里概述的研究将增加我们对介导免疫抑制和宿主抗微生物防御抗性的重要毒力因子的理解。这些蛋白质是有吸引力的抑制新药靶点，因为它们可能与抗生素协同作用，同时增强免疫介导的Mtb杀伤作用。