Whole genome sequencing of Mycobacterium tuberculosis reveals slow growth and low mutation rates during latent infections in humans.
Whole genome sequencing of Mycobacterium tuberculosis reveals slow growth and low mutation rates during latent infections in humans.
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DOI：
10.1371/journal.pone.0091024
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Alland D
中科院分区：
文献类型：
--
作者：
Colangeli R;Arcus VL;Cursons RT;Ruthe A;Karalus N;Coley K;Manning SD;Kim S;Marchiano E;Alland D
关于结核分枝杆菌在人类潜伏感染期间的生长和突变率，人们知之甚少。然而，对恒河猴的研究表明，潜伏感染的变异率高于在活动性结核病期间观察到的变异率。突变率升高被认为是产生抗药性的危险因素。因此，研究人类潜伏期的突变率具有重要意义。我们对新西兰Rangipo菌株数十年的结核病暴发中分离的结核分枝杆菌分离株进行了全基因组突变分析。我们使用流行病学和系统发育分析来鉴定从同一指标性病例获得的四例结核病。其中两例结核病病例发生在接触后两年内，并被归类为最近传播的结核病。另外两例发生在暴露20多年后，被归类为潜伏的结核分枝杆菌感染重新激活。比较了最近传输的两对与两个潜伏的对之间的突变率。假设世代时间为20小时，新发结核病的平均突变率为5.5X10−10突变/个/代，潜伏结核病为7.3X10个−11突变/个/代。在所有复制率中，新近传播的结核病的世代时间对突变率的曲线也显著更高(p = 0.006)。假设在疾病复发前的最后两年，所有分离株的复制和突变率相同，则可归因于剩余潜伏期的u20hr突变率为1.6x10−11突变/代，或比紧接发病前两年计算的u20hr突变率低约30倍。细菌暴露于宿主免疫系统可能导致的氧化应激突变在潜伏感染中没有增加。总而言之，我们没有发现任何证据表明，与恒河猴的情况不同，人类在结核病潜伏期内突变率升高。
Very little is known about the growth and mutation rates of Mycobacterium tuberculosis during latent infection in humans. However, studies in rhesus macaques have suggested that latent infections have mutation rates that are higher than that observed during active tuberculosis disease. Elevated mutation rates are presumed risk factors for the development of drug resistance. Therefore, the investigation of mutation rates during human latency is of high importance. We performed whole genome mutation analysis of M. tuberculosis isolates from a multi-decade tuberculosis outbreak of the New Zealand Rangipo strain. We used epidemiological and phylogenetic analysis to identify four cases of tuberculosis acquired from the same index case. Two of the tuberculosis cases occurred within two years of exposure and were classified as recently transmitted tuberculosis. Two other cases occurred more than 20 years after exposure and were classified as reactivation of latent M. tuberculosis infections. Mutation rates were compared between the two recently transmitted pairs versus the two latent pairs. Mean mutation rates assuming 20 hour generation times were 5.5X10−10 mutations/bp/generation for recently transmitted tuberculosis and 7.3X10−11 mutations/bp/generation for latent tuberculosis. Generation time versus mutation rate curves were also significantly higher for recently transmitted tuberculosis across all replication rates (p = 0.006). Assuming identical replication and mutation rates among all isolates in the final two years before disease reactivation, the u20hr mutation rate attributable to the remaining latent period was 1.6×10−11 mutations/bp/generation, or approximately 30 fold less than that calculated during the two years immediately before disease. Mutations attributable to oxidative stress as might be caused by bacterial exposure to the host immune system were not increased in latent infections. In conclusion, we did not find any evidence to suggest elevated mutation rates during tuberculosis latency in humans, unlike the situation in rhesus macaques.
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