Marquis Jean-François, Lacourse Ronald, Ryan Lynn, North Robert J, Gros Philippe
Department of Biochemistry, Centre for the Study of Host Resistance, McGill University, Montréal, Québec, Canada.
J Immunol. 2009 Mar 15;182(6):3757-67. doi: 10.4049/jimmunol.0802094.
The genetic control of susceptibility to tuberculosis in DBA/2J and C57BL/6J mice is complex and influenced by at least four tuberculosis resistance loci (Trl1-Trl4). To further study the Trl3 and Trl4 loci, we have created congenic mouse lines D2.B6-Chr7 and D2.B6-Chr19, in which resistant B6-derived portions of chromosome 7 (Chr.7) and chromosome 19 (Chr.19) overlapping Trl3 and Trl4, respectively, were independently introgressed onto susceptible D2 background. Transfer of B6-derived Trl3 chromosome 7 segment significantly increased resistance of D2 mice, as measured by reduced pulmonary microbial replication at day 70, and increased host survival following aerosol infection. However, transfer of B6-derived chromosome 19 (Trl4) onto D2 mice did not increase resistance by itself and does not improve on the protective effect of chromosome 7. Further study of the protective effect of Trl3 in D2.B6-Chr7 mice indicates that it does not involve modulation of timing or magnitude of Th1 response in the lung, as investigated by measuring the number of Ag-specific, IFN-gamma-producing CD4(+) and CD8(+) T cells. Rather, Trl3 appears to affect the intrinsic ability of activated macrophages to restrict intracellular mycobacterial replication in an NO synthase 2-independent fashion. Microarray experiments involving parental and congenic mouse lines identified a number of genes in the Trl3 interval on chromosome 7 the level of expression of which before infection or in response to Mycobacterium tuberculosis infection is differentially regulated in a parental haplotype-dependent fashion. This gene list represents a valuable entry point for the identification and prioritization of positional candidate genes for the Trl3 effect on chromosome 7.
DBA/2J和C57BL/6J小鼠对结核病易感性的遗传控制很复杂，至少受四个结核病抗性基因座（Trl1 - Trl4）影响。为了进一步研究Trl3和Trl4基因座，我们培育了同类系小鼠D2.B6 - Chr7和D2.B6 - Chr19，其中分别与Trl3和Trl4重叠的7号染色体（Chr.7）和19号染色体（Chr.19）上源自B6的抗性部分被独立导入到易感性D2背景中。将源自B6的Trl3 7号染色体片段进行转移，显著提高了D2小鼠的抗性，这通过在第70天时肺部微生物复制减少以及气溶胶感染后宿主存活率增加来衡量。然而，将源自B6的19号染色体（Trl4）转移到D2小鼠上本身并未增加抗性，也没有增强7号染色体的保护作用。对D2.B6 - Chr7小鼠中Trl3保护作用的进一步研究表明，它不涉及对肺部Th1反应的时间或强度的调节，这是通过测量抗原特异性、产生IFN - γ的CD4(+)和CD8(+) T细胞数量来研究的。相反，Trl3似乎以一种不依赖于一氧化氮合酶2的方式影响活化巨噬细胞限制细胞内分枝杆菌复制的内在能力。涉及亲本和同类系小鼠品系的微阵列实验在7号染色体上的Trl3区间鉴定出了许多基因，这些基因在感染前或对结核分枝杆菌感染的反应中，其表达水平以亲本单倍型依赖的方式受到差异调节。这个基因列表是鉴定和确定7号染色体上Trl3效应的位置候选基因优先级的有价值切入点。
