Host-Pathogen Interactions in a Failing Global lineage of MTBC:M.africanum

MTBC 失败的全球谱系中宿主与病原体的相互作用：M.africanum

基本信息

批准号：
8664215
负责人：
Souleymane Diallo
金额：
$ 57.65万
依托单位：
UNIV OF SCIENCES, TECH & TECH OF BAMAKO
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-04-01 至 2019-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8664215
关键词：
AIDS clinical trial group Accounting Address Adenylate Cyclase Advanced Development Africa African Alleles Antitubercular Agents Automobile Driving Cells Clinical Complex Cyclic AMP Data Development Disease Drug resistance Environmental Risk Factor Epidemic Epitopes Ethnic Origin Extramural Activities Failure Gambia Genes Genetic Genomic DNA Genotype Genus Mycobacterium Ghana HIV Haplotypes Head Health High Prevalence Host Defense Household Human Immune response Immunity Incidence Individual Infection Institutes Integration Host Factors Interferons International International AIDS Intoxication Investigation Laboratories Lead Malaria Mali Maryland Medical Modeling Molecular Multi-Drug Resistance Mycobacterium tuberculosis National Institute of Allergy and Infectious Disease New York Outcome Pathogenicity Patients Pharmaceutical Preparations Population Prevalence Public Health Publishing Pulmonary Tuberculosis Qualifying RNA RNA Sequences Relative (related person)Reporting Research Research Infrastructure Research Training Resistance Resources Retreatment T-Lymphocyte Epitopes Testing Therapeutic Training Transcript Tuberculosis Tumor Necrosis Factor-alpha United States National Institutes of Health Universities Urbanization Vaccines Virulence Whole Blood antimicrobial peptide attenuation base global health improved in vivo international center killings member mortality mutant mycobacterial novel vaccines pathogen patient population preference professor programs therapeutic vaccine transcriptomics tuberculosis drugs

项目摘要

DESCRIPTION (provided by applicant): Tuberculosis (TB) remains a public health problem in resource-limited settings such as Mali, West Africa. In 2011, WHO estimated the prevalence, incidence and mortality from TB in Mali was 90, 62 and 9 per 100,000 population. There is considerable variability in the outcome of Mycobacterium tuberculosis complex (MTBC) infection which has been traditionally attributed to host and environmental factors. MTBC is composed of 8 subspecies. Clinical TB disease in humans is caused mainly by M tuberculosis and M africanum. Recently, we identified by spoligotyping that M africanum and M tuberculosis are the most prevalent strains in Mali as they are throughout West Africa, respectively accounting for 27.8 and 71.4% of TB cases. In humans, both species transmit equally well to household contacts, however M africanum is less likely to progress to clinical disease, less likely to be multidrug resistant, and patients with disease are more likely to be malnourished, older, or have co-infection with HIV, suggesting it has a preference for hosts with certain genetic backgrounds and/or with impaired immunity. The immune response to TB is complex and not yet characterized completely which is making it difficult to develop new vaccines and drugs. Taken altogether, the fact that M africanum has not spread beyond West Africa, that it has decreased virulence in vivo, and has predilection for immuno-compromised individuals, strongly suggests that it is a failing pathogen on a global level. A research strategy that investigates host immune responses with pathogen factors may reveal critical aspects of host immunity and mycobacterial pathogenicity. The specific aims of this project are: 1) test a model of sympatric TB, based on associations of specific HLA alleles and bacterial strain-dependent T cell epitope sequences; 2) characterize human phenotypic consequences from loss of cAMP intoxication virulence mechanism in M africanum, reductions in TNF-α and antimicrobial peptide expression; and 3) identify host transcriptomic factors that differentiate active infection with M tuberculosis from M africanum. Professor Diallo, head of the TB program in Mali, and the SEREFO Laboratory team at the University of Bamako are highly qualified to lead this proposal. SEREFO was established in 2005 by National Institutes of Allergy and Infectious Diseases (NIAID) under the direction of Dr. Cliff Lane. The program has become an NIAID International Center for the Excellence in Research (ICER) and is supported by extramural programs including the University of Maryland BMP Project, International Network for Strategic Initiatives in Global Health (INSIGHT-the START Study), the International Center for Malaria Research (ICEMRS) and the AIDS Clinical Trials Group (ACTG). The Fogarty International Center/NIH has trained many of the research staff through its AIDS International Training and Research Program (AITRP) based at Northwestern University. Other key collaborators include Johns Hopkins University, New York University, the Howard Hughes Medical Institute. The overarching intent of this project will advance the development of local scientific expertise, build local research infrastructure and increase collaborative research partnerships in Mali.

描述（由申请人提供）：在西非马里等资源有限的地区，结核病 (TB) 仍然是一个公共卫生问题。 2011 年，世卫组织估计马里结核病患病率、发病率和死亡率分别为 90 例、62 例和 9 例。 100,000 人群中结核分枝杆菌复合体 (MTBC) 感染的结果存在很大差异，传统上将其归因于宿主和环境因素。人类临床结核病主要由结核分枝杆菌和非洲分枝杆菌引起，最近，我们通过 spoligotyping 确定，非洲分枝杆菌和结核分枝杆菌是马里最流行的菌株，因为它们分别占整个西非。在人类中，分别有 27.8% 和 71.4% 的结核病病例传播给家庭接触者，但非洲分枝杆菌进展为临床疾病的可能性较小。具有多重耐药性，患病患者更有可能营养不良、年龄较大或同时感染艾滋病毒，这表明它偏爱具有某些遗传背景和/或免疫力受损的宿主。对结核病的免疫反应是复杂的。且尚未完全表征，这使得开发新疫苗和药物变得困难。总而言之，非洲分枝杆菌尚未传播到西非以外的地区，它在体内的毒力已降低，并且对病毒有偏好。免疫功能低下的个体，强烈表明它是一种全球范围内失败的病原体。一项研究病原体因子的宿主免疫反应的研究策略可能揭示宿主免疫和分枝杆菌致病性的关键方面。该项目的具体目标是：1)基于特定 HLA 等位基因和细菌菌株依赖性 T 细胞表位序列的关联，测试同域结核病模型 2) 表征 M 中 cAMP 中毒毒力机制丧失的人类表型后果； africanum，TNF-α 和抗菌肽表达的减少；3) 确定区分结核分枝杆菌活动性感染和结核分枝杆菌的宿主转录组因子； africanum 教授是马里结核病项目的负责人，他和巴马科大学的 SEREFO 实验室团队非常有资格领导这项提案。SEREFO 是在国家过敏和传染病研究所 (NIAID) 的指导下于 2005 年建立的。该项目已成为 NIAID 国际卓越研究中心 (ICER)，并得到包括马里兰大学 BMP 项目、国际项目在内的校外项目的支持。全球健康战略倡议网络（INSIGHT-START 研究）、国际疟疾研究中心 (ICEMRS) 和艾滋病临床试验小组 (ACTG) 福格蒂国际中心/NIH 通过其艾滋病培训了许多研究人员。西北大学的国际培训和研究计划（AITRP）其他主要合作者包括约翰·霍普金斯大学、纽约大学、霍华德休斯医学研究所。该项目的总体目标是促进当地科学专业知识的发展，建立当地研究。基础设施建设并加强马里的合作研究伙伴关系。