Interplay of strain and ethnicity in the immune response to M. tuberculosis

结核分枝杆菌免疫反应中菌株和种族的相互作用

基本信息

批准号：
7500655
负责人：
PAYAM NAHID
金额：
$ 12.42万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-09-28 至 2012-08-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Genotyping of Mycobacterium tuberculosis has shown that specific geographic regions are dominated by genetically distinct genotypes of Mycobacterium tuberculosis. This global distribution of strains, such as that seen with the Beijing family, may not be random or solely based upon virulence, socioeconomics, or geography but may be partly determined by the genetics of the host and the microbe, both of which are under environmental and natural selection forces. In this proposal, we hypothesize that such forces have played a role in the co-evolution of host and microbe, such that ethnic-specific susceptibility and resistance exists for particular strains of M. tuberculosis. This interplay between the strain and the ethnic background of the host is plausible, given that susceptibility to and outcome of infection with M. tuberculosis appears to vary with ethnic background and that a strong association between specific ethnic backgrounds and specific strains has been noted in urban settings outside of the host's native country. In the research proposed herein, we will measure and compare the cytokine repertoire produced by cells from subjects of different ethnicities in response to lysates of different strains of M. tuberculosis to determine the ability of various strains of M. tuberculosis to evade protective innate and adaptive immune mechanisms - possibly by selective induction of anti-inflammatory cytokines. We plan to accomplish this by evaluating the immune response of healthy human donor macrophages to a Beijing strain (HN878), a Manila strain (T31), a clinical strain isolated in the US (CDC1551), and a laboratory reference strain (H37Rv), as well as by evaluating the effect of these same strains in an integrative, whole blood assay. We will stratify the donors by ethnicity, looking for the presence of ethnic-specific immunogenetic predisposition to distinct strains of M. tuberculosis. This research aims to establish whether the genetically diverse strains of M. tuberculosis induce different innate and adaptive responses amongst and between select ethnicities, and thus pave the way for tailoring vaccines to specific populations. I have assembled a mentoring committee of internationally recognized scientists with strong track records in the study of tuberculosis, particularly in molecular genotyping (Dr. Philip Hopewell - primary mentor) and immunology (Dr. David Lewinsohn) of M. tuberculosis, and in admixture analysis (Dr. Neil Risch) and epidemiology (Drs. Dennis Osmond and Neil Risch). Together, these senior investigators represent the diversity of fields that are essential for my training and proposed research study.

描述（由申请人提供）：结核分枝杆菌的基因分型表明，特定的地理区域由结核分枝杆菌的遗传学基因型主导。这种菌株的全球分布，例如在北京家族中看到的菌株，可能不是随机的，也不是基于毒力，社会经济学或地理位置，但可能部分由宿主和微生物的遗传学决定，这两者都是在环境和自然选择的下。在该提案中，我们假设这种力在宿主和微生物的共同进化中发挥了作用，因此特定于种族特异性的敏感性和对结核分枝杆菌菌株的抗药性。鉴于宿主的菌株和种族背景之间的这种相互作用是合理的，因为对结核分枝杆菌的敏感性和感染的敏感性似乎随族裔背景而变化，并且在宿主国外之外的城市环境中已经指出了特定种族背景与特定菌株之间的密切相关性。在本文提出的研究中，我们将测量和比较来自不同种族受试者产生的细胞因子库，以响应不同的结核分枝杆菌菌株的裂解物，以确定结核分枝杆菌的各种菌株的能力，以逃避保护性的先天性和适应性免疫机制 - 可能通过选择性地诱导抗抗毒素cytokine cytokine cytokine cytokine cytokine cytokine。我们计划通过评估健康的人类供体巨噬细胞对北京菌株的免疫反应（HN878），马尼拉菌株（T31），在美国分离的临床菌株（CDC1551）和实验室参考菌株（H37RV）的免疫反应，以及通过对这些集成的效果进行评估。我们将根据种族对捐助者进行分层，以寻找对结核分枝杆菌的不同菌株的种族特异性免疫遗传。这项研究旨在确定结核分枝杆菌的遗传多样性是否会在精选的种族之间以及在某些种族之间引起不同的先天和适应性反应，从而为特定人群的疫苗定制疫苗铺平了道路。在结核病研究中，我组建了一个国际认可的科学家指导委员会，尤其是在分子基因分型（Philip Hopewell-博士 - 主要导师）和免疫学（David Lewinsohn博士）的结核病（David Lewinsohn博士），以及Amdixuture分析（Neil Risch）和Epidemiology（Dris）和dennis Osmond ands Osmond riss osmond。这些高级研究人员共同代表了我的培训和拟议研究至关重要的领域的多样性。