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

描述(由申请人提供)：结核分枝杆菌的基因分型表明，特定的地理区域由不同的结核分枝杆菌基因类型主导。这种菌株的全球分布，如北京家族的菌株，可能不是随机的，也不是完全基于毒力、社会经济或地理环境，但可能部分取决于宿主和微生物的遗传，这两者都受到环境和自然选择的影响。在这项提议中，我们假设这些力量在宿主和微生物的共同进化中发挥了作用，从而使特定的结核分枝杆菌株存在种族特异性的易感性和耐药性。考虑到结核分枝杆菌感染的易感性和结果似乎因种族背景而异，而且在宿主国家以外的城市环境中，特定的种族背景和特定的菌株之间存在着强烈的联系，这种菌株与宿主的种族背景之间的相互作用是可信的。在本文提出的研究中，我们将测量和比较不同种族的受试者细胞对不同株结核分枝杆菌裂解物产生的细胞因子谱，以确定不同株结核分枝杆菌逃避保护性先天性和获得性免疫机制的能力-可能是通过选择性地诱导抗炎细胞因子。我们计划通过评估健康的人类供体巨噬细胞对北京病毒株(HN878)、马尼拉病毒株(T31)、美国临床病毒株(CDC1551)和实验室参考病毒株(H37Rv)的免疫反应，以及通过综合全血检测来评估这些相同菌株的效果。我们将按种族对捐赠者进行分层，寻找对不同结核分枝杆菌菌株具有种族特异性免疫遗传易感性的存在。这项研究旨在确定遗传多样性的结核分枝杆菌菌株是否会在选定的种族之间产生不同的先天和适应性反应，从而为针对特定人群定制疫苗铺平道路。我组建了一个由国际知名科学家组成的指导委员会，他们在结核病研究方面有良好的记录，特别是在结核病的分子基因分型(菲利普·霍普韦尔博士-主要导师)和免疫学(大卫·莱温松博士)，以及混合分析(尼尔·里施博士)和流行病学(丹尼斯·奥斯蒙德博士和尼尔·里希博士)方面。总的来说，这些高级研究员代表了对我的培训和拟议的研究性学习至关重要的不同领域。

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.