Domenech Pilar, Reed Michael B, Barry Clifton E
Tuberculosis Research Section, Laboratory of Immunogenetics, 12441 Parklawn Drive, Rockville, MD 20852, USA.
Infect Immun. 2005 Jun;73(6):3492-501. doi: 10.1128/IAI.73.6.3492-3501.2005.
The genome sequence of Mycobacterium tuberculosis revealed the presence of 12 membrane proteins proposed to have a function in the transport of lipids. Insertional inactivation of 11 of these has revealed that only 1 (MmpL3) is apparently essential for viability. Five of these proteins are conserved within the genome of Mycobacterium leprae. The drug susceptibilities of these 11 mutants to a broad spectrum of agents are unaltered, suggesting that unlike their function in other organisms, these proteins do not play a significant role in intrinsic drug resistance. Each of these mutants was assessed for growth kinetics and lethality in a murine low-dose aerosol model of tuberculosis, and four were found to be impaired in one or both measures of virulence. Two of these, with mutations of MmpL4 and the previously characterized MmpL7, which transports phthiocerol dimycocerosate, were found to have both impaired growth kinetics and impaired lethality. Mutants with inactivation of MmpL8, which transports a precursor of the sulfatides, or MmpL11, which transports an unknown substrate, were found to establish infection normally but to be significantly attenuated for lethality in time-to-death studies. These studies support the concept that MmpL-mediated lipid secretion both contributes to the innate ability of the pathogen to survive intracellularly and also contributes directly to the host-pathogen dialogue that determines the ultimate outcome of infection.
结核分枝杆菌的基因组序列显示存在12种被认为在脂质转运中起作用的膜蛋白。对其中11种进行插入失活研究发现，只有1种（MmpL3）显然对生存力至关重要。这些蛋白中有5种在麻风分枝杆菌基因组中是保守的。这11个突变体对多种药物的敏感性未发生改变，这表明与它们在其他生物体中的功能不同，这些蛋白在固有耐药性方面不发挥重要作用。在小鼠低剂量气溶胶结核病模型中评估了每个突变体的生长动力学和致死性，发现其中4个在一项或两项毒力指标上受损。其中两个，即MmpL4发生突变的突变体和先前已表征的转运二分枝菌酸酚酯的MmpL7发生突变的突变体，被发现生长动力学和致死性均受损。转运硫脂前体的MmpL8或转运未知底物的MmpL11失活的突变体，在感染建立方面正常，但在致死性时间-死亡研究中明显减毒。这些研究支持了这样一种观点，即MmpL介导的脂质分泌既有助于病原体在细胞内存活的固有能力，也直接有助于决定感染最终结果的宿主-病原体对话。
