Little is known about the physiology of latent Mycobacterium tuberculosis infection. We studied the mutational rates of 24 index tuberculosis (TB) cases and their latently infected household contacts who developed active TB up to 5.25 years later, as an indication of bacterial physiological state and possible generation times during latent TB infection in humans. Here we report that the rate of new mutations in the M. tuberculosis genome decline dramatically after two years of latent infection (two-sided p < 0.001, assuming an 18 h generation time equal to log phase M. tuberculosis, with latency period modeled as a continuous variable). Alternatively, assuming a fixed mutation rate, the generation time increases over the latency duration. Mutations indicative of oxidative stress do not increase with increasing latency duration suggesting a lack of host or bacterial derived mutational stress. These results suggest that M. tuberculosis enters a quiescent state during latency, decreasing the risk for mutational drug resistance and increasing generation time, but potentially increasing bacterial tolerance to drugs that target actively growing bacteria.

关于潜伏结核分枝杆菌感染的生理学知之甚少。我们研究了 24 例结核病 (TB) 病例及其潜伏感染的家庭接触者在长达 5.25 年后发展为活动性结核病的突变率，作为人类潜伏性结核病感染期间细菌生理状态和可能的世代时间的指标。在这里，我们报告说，潜伏感染两年后，结核分枝杆菌基因组中的新突变率急剧下降（双侧 p < 0.001，假设 18 小时的世代时间等于对数期结核分枝杆菌，潜伏期建模）作为连续变量）。或者，假设突变率固定，生成时间会随着等待时间的推移而增加。指示氧化应激的突变不会随着潜伏期的增加而增加，表明缺乏宿主或细菌衍生的突变应激。这些结果表明，结核分枝杆菌在潜伏期进入静止状态，降低了突变耐药性的风险并增加了世代时间，但可能增加了细菌对针对活跃生长细菌的药物的耐受性。