Genetic control of resistance to experimental infection with virulent Mycobacterium tuberculosis
Genetic control of resistance to experimental infection with virulent Mycobacterium tuberculosis
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DOI：
10.1073/pnas.150227197
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发表时间：
2000-07-18
影响因子：
11.1
通讯作者：
Bloom, BR
中科院分区：
文献类型：
--
作者：
Kramnik, I;Dietrich, WF;Bloom, BR
据估计，超过20亿人感染了致命的结核分枝杆菌，但在他们的一生中，只有不到10%的人发展为临床结核病。双胞胎研究和暴露于类似环境风险后结核病感染结果的变化表明，个体对疾病的易感性存在遗传异质性。在小鼠结核病模型中，我们已经建立了对毒性M.结核病是一种复杂的遗传特征。一个对结核病易感性有重要影响的新位点，命名为sst 1（对结核病的易感性1），被定位在小鼠1号染色体上的9厘摩（cM）间隔上。它位于先前鉴定的基因Nramp 1远端10-19 cM处。控制小鼠对减毒卡介苗疫苗株的先天抗性。新鉴定的基因座的表型表达与Nramp 1的表型表达不同，因为sst 1以肺特异性方式控制结核感染的进展。在sst 1位点分离的小鼠在肺中毒性结核杆菌的生长速率上表现出显著的差异。同系sst 1敏感小鼠的肺部病变特征为广泛坏死和毒性分枝杆菌的细胞外不受限制的增殖，而sst 1耐药小鼠发生间质性肉芽肿，并有效地控制了杆菌的增殖。sst 1的抗性等位基因，虽然在控制感染方面很强大，但不足以提供对强毒M的完全保护。结核这表明位于SST 1基因座之外的其它基因对于控制结核病感染也可能是重要的。
Over 2 billion people are estimated to be infected with virulent Mycobacterium tuberculosis, yet fewer than 10% progress to clinical tuberculosis within their lifetime. Twin studies and variations in the outcome of tuberculosis infection after exposure to similar environmental risks suggest genetic heterogeneity among individuals in their susceptibility to disease. In a mouse model of tuberculosis, we have established that resistance and susceptibility to virulent M. tuberculosis is a complex genetic trait. A new locus with a major effect on tuberculosis susceptibility, designated sst1 (susceptibility to tuberculosis 1), was mapped to a 9-centimorgan (cM) interval on mouse chromosome 1. It is located 10-19 cM distal to a previously identified gene, Nramp1. that controls the innate resistance of mice to the attenuated bacillus Calmette-Guerin vaccine strain. The phenotypic expression of the newly identified locus is distinct from that of Nramp1 in that sst1 controls progression of tuberculosis infection in a lung-specific manner. Mice segregating at the sst1 locus exhibit marked differences in the growth rates of virulent tubercle bacilli in the lungs. Lung lesions in congenic sst1-susceptible mice are characterized by extensive necrosis and unrestricted extracellular multiplication of virulent mycobacteria, whereas sst1-resistant mice develop interstitial granulomas and effectively control multiplication of the bacilli. The resistant allele of sst1, although powerful in controlling infection, is not sufficient to confer full protection against virulent M. tuberculosis. indicating that other genes located outside of the sst1 locus are likely also to he important for controlling tuberculosis infection.