GENETIC DISSECTION OF MYCOBACTERIAL INFECTION

描述(由申请人提供) 本申请中提出的研究的目标是确定 小鼠和分枝杆菌的基因组合导致显著 寄主对实验性分枝杆菌感染反应的改变。 对实验性感染的易感性或抵抗力将由 中位生存时间、体重减轻、分枝杆菌负荷的测定 肺和脾，以及肺和脾的各种免疫学参数 其他纸巾。在这些实验中，宿主基因组将通过使用 37个来自近交系的重组同源菌株(RC) 易患结核病的祖细胞(A/J，缩写A) 或对结核病耐药(C57BL/6J，缩写B)。ACB/BCA RCS为 现在完全近亲繁殖并通过密集的全基因组微卫星集进行基因分型 记号笔。这些菌株将被一组分枝杆菌感染 基因组区域缺失的结核分枝杆菌和牛分枝杆菌 与卡介苗减毒有关。医院中的感染方案 RCS将揭示与“预期”或 表示数量性状存在的“亲本”疾病表型 对表型表达有很强影响的座位(QTL)，可能是特异的 寄主与病原菌之间的基因互作(S)。在携带QTL的RCS中 对表型表达有强烈影响，基因表达水平变化 肺巨噬细胞和细胞内分枝杆菌都将通过 微阵列分析。了解宿主在多大程度上做出响应 分枝杆菌感染是特定宿主病原体的反映 组合对于我们理解流行病学流动是至关重要的。 通过暴露人群传播结核分枝杆菌。

DESCRIPTION (provided by applicant) The objective of the studies proposed in this application is to identify genotypic combinations of mice and mycobacteria that result in significant alterations of host responses to experimental mycobacterial infection. Susceptibility or resistance to experimental infection will be defined by determination of median survival time, weight loss, mycobacterial load in the lung and spleen, and in addition various immunological parameters in lung and other tissues. In these experiments, the host genome will be varied by use of 37 recombinant congenic strains (RCS), which are derived from inbred progenitors that are either susceptible to tuberculosis (A/J, abbreviated A) or resistant to tuberculosis (C57BL/6J, abbreviated B). The AcB/BcA RCS are now fully inbred and genotyped with a dense set of genome-wide microsatellite markers. These strains will be infected with a panel of Mycobacterium tuberculosis and M. bovis strains that have been deleted for genome regions associated with attenuation of BCG vaccines. The infection protocol in the RCS will reveal informative, significant deviations from the "expected" or "parental" disease phenotypes which signify the presence of quantitative trait loci (QTL) with strong effect on phenotype expression and possibly specific gene(s) interaction between the host and pathogen. In RCS carrying QTL with strong effect on phenotype expression, changes in gene expression level in both lung macrophages and intracellular mycobacteria will be revealed by microarray analysis. The knowledge to what extent host responses in mycobacterial infections are a reflection of specific host pathogen combinations will be crucial for our understanding of the epidemiological flow of M. tuberculosis through an exposed population.