Genetic Requirements for the survival of Tubercle Bacilli in Nonhuman Primates

非人灵长类结核杆菌生存的遗传要求

• 批准号: 8473655
• 负责人: Deepak Kaushal
• 金额: $ 73.04万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-06-01 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8473655
• 关键词: Acquired Immunodeficiency Syndrome; Acute; Address; Aerosols; Age; Alveolar; Anabolism; Animals; Antitubercular Agents; Attenuated; Autopsy; Bacillus (bacterium); Belief; Biological Assay; Body Temperature; C-reactive protein; CCL19 gene; CCL2 gene; CCL7 gene; CD4 Positive T Lymphocytes; Catabolism; Cavia; Cell Wall; Cells; Cessation of life; Characteristics; Cholesterol; Chromosomes; Chronic; Clinical; Communicable Diseases; Confocal Microscopy; DNA Repair; Defect; Development; Disease; Dose; Drug resistance; Emergency Situation; Environment; Enzyme-Linked Immunosorbent Assay; Exhibits; Failure; Family; Fatty Acids; Genes; Genetic; Genome; Granuloma; Granulomatous; Growth; Histopathology; Human; Hypersensitivity skin testing; Hypoxia; Immune system; In Situ Hybridization; Individual; Infection; Inflammatory; Interleukin-12; Irrigation; Lesion; Libraries; Liver; Lung; Lung Lavage Fluid; Macaca mulatta; Mammalian Cell; Measurement; Measures; Metabolism; Minority; Modeling; Monkeys; Mus; Mycobacterium tuberculosis; Nitrate Reductases; Nutrient; Operon; Output; Pathogenesis; Pathology; Pathway interactions; Peptidoglycan; Pharmaceutical Preparations; Phase; Phenotype; Phosphotransferases; Physiological; Play; Primates; Process; Production; Pulmonary Tuberculosis; Regulon; Relative (related person); Reporting; Resistance; Rest; Reverse Transcriptase Polymerase Chain Reaction; Role; Sampling; Serum; Simian Acquired Immunodeficiency Syndrome; Southern Blotting; Spleen; Staging; Sterols; Stress; System; Testing; Time; Tuberculosis; Tuberculosis Vaccines; Vaccines; Validation; Virulence; Virulence Factors; Virulent; Weight; araban; attenuation; base; hygromycin A; immune activation; immunopathology; in vivo; lipid transport; lymph nodes; macrophage; male; member; mortality; mouse model; mutant; nitrate reductase; nonhuman primate; peripheral blood; public health relevance; research study; response; sensor; transposon site hybridization; tuberculosis drugs; vector

DESCRIPTION (provided by applicant): Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), is a global infectious disease emergency. Each year an estimated 8 million people develop, and about two million people die of TB. Synergy with AIDS, the emergence of drug-resistance and the lack of effective anti-TB drugs and vaccines has worsened this situation. New drugs and vaccines are urgently needed to effectively control TB. This requires a better understanding of how Mtb adapts to a wide-variety of environmental conditions, inevitably faced by it during the various stages of infection. Nonhuman Primates (NHPs), arguably, best model critical aspects of TB. Analysis of the mechanisms employed by Mtb to successfully infect and persist in NHP lungs would therefore be very useful. We studied genes essential for growth/survival of Mtb in the NHP lungs experimentally exposed to high doses of aerosols of an Mtb transposon mutant library. In this acute model of TB, 33.13% of all tested mutants were attenuated for in-vivo growth compared to the mouse model where only ~6% of all mutants are attenuated. The Mtb mutants attenuated for in-vivo survival in primates were involved in the transport of lipid virulence factors; biosynthesis of cell-wall arabinan and peptidoglycan, fatty-acids and polyketides; DNA repair; sterol metabolism and mammalian cell-entry (mce). Our study highlights the various virulence-mechanisms employed by Mtb for infection and to overcome the hostile environment encountered during infection of NHP lungs. We would like to leverage our ability to model the various clinical phases of human TB - acute, pulmonary TB, chronic-progressive TB and latent, asymptomatic TB in NHPs - to study the growth/survival phenotype profiles of Mtb mutants. Further, we would like to better understand the role of two Mtb pathways crucial for virulence and pathogenesis, using the NHP model. These include the mce1/mce4 operons, whose members were among mutants that were attenuated for growth in NHP lungs; and members of the dos regulon, which were surprisingly not attenuated in NHP lungs, in-spite of their well-defined roles in latency, persistence and defense against hypoxia.

描述（由申请人提供）：结核分枝杆菌（MTB）引起的结核病（TB）是全球感染病紧急情况。每年估计有800万人出现，约有200万人死于结核病。与艾滋病的协同作用，抗药性的出现以及缺乏有效的抗TB药物和疫苗的情况使这种情况恶化了。迫切需要新药和疫苗有效控制结核病。这需要更好地了解MTB如何适应各种环境条件，在感染的各个阶段，它不可避免地面临。可以说，非人类灵长类动物（NHP）是结核病的最佳模型关键方面。因此，对MTB成功感染和持续在NHP肺中使用的机制的分析将非常有用。我们研究了MTB肺中MTB生长/存活至关重要的基因，该基因在实验中暴露于MTB转座子突变库中的高剂量气溶胶。在这种结核病的急性模型中，与小鼠模型相比，所有测试突变体中有33.13％的体内生长被衰减，而小鼠模型只有约6％的突变体被衰减。在灵长类动物的体内存活中，MTB突变体参与了脂质毒力因子的运输。细胞壁阿拉伯糖和肽聚糖，脂肪酸和聚酮化合物的生物合成； DNA修复；固醇代谢和哺乳动物细胞进入（MCE）。我们的研究强调了MTB用于感染的各种毒力机制，并克服了NHP肺部感染期间遇到的敌对环境。我们想利用对人类结核的各种临床阶段进行建模的能力 - 急性，肺结核，慢性促进性结核病和潜在的NHP中无症状TB - 研究MTB突变体的生长/存活表型。此外，我们希望更好地理解使用NHP模型对毒力和发病机理至关重要的两种MTB途径的作用。其中包括MCE1/MCE4操纵子，其成员属于NHP肺增长的突变体之一； DOS Regulon的成员，令人惊讶的是，NHP肺部没有衰减，他们在延迟，持久性和防御性缺氧方面发挥了明确的作用。