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Deletion of a mycobacterial divisome factor collapses single-cell phenotypic heterogeneity

机译：分枝杆菌除体因子的删除使单细胞表型异质性崩溃

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摘要

Microorganisms are often studied as populations but the behaviour of single, individual cells can have important consequences. For example, tuberculosis, caused by the bacterial pathogen Mycobacterium tuberculosis, requires months of antibiotic therapy even though the bulk of the bacterial population dies rapidly. Shorter courses lead to high rates of relapse because subpopulations of bacilli can survive despite being genetically identical to those that are easily killed(1). In fact, mycobacteria create variability each time a cell divides, producing daughter cells with different sizes and growth rates(2,3). The mechanism(s) that underlie this high-frequency variation and how variability relates to survival of the population are unknown. Here we show that mycobacteria actively create heterogeneity. Using a fluorescent reporter and a fluorescence-activated cell sorting (FACS)-based transposon screen, we find that deletion of lamA, a gene of previously unknown function, decreases heterogeneity in the population by decreasing asymmetric polar growth. LamA has no known homologues in other organisms, but is highly conserved across mycobacterial species. We find that LamA is a member of the mycobacterial division complex (the 'divisome'). It inhibits growth at nascent new poles, creating asymmetry in polar growth. The kinetics of killing individual cells that lack lamA are more uniform and more rapid with rifampicin and drugs that target the cell wall. Our results show that mycobacteria encode a non-conserved protein that controls the pattern of cell growth, resulting in a population that is both heterogeneous and better able to survive antibiotic pressure.
机译：微生物通常以种群的形式进行研究，但是单个，单个细胞的行为可能会产生重要的后果。例如，由细菌病原体结核分枝杆菌引起的结核病需要数月的抗生素治疗，即使大部分细菌种群迅速死亡。较短的疗程会导致较高的复发率，因为尽管细菌亚群在遗传上与容易杀死的亚群相同，但它们仍可以存活（1）。实际上，分枝杆菌每次细胞分裂都会产生变异性，产生大小和增长率不同的子细胞（2,3）。造成这种高频变化的机制以及变异性与种群生存的关系尚不清楚。在这里，我们显示分枝杆菌积极地产生异质性。使用基于荧光报告基因和基于荧光激活细胞分选（FACS）的转座子筛选，我们发现lamA（一种先前未知功能的基因）的缺失通过减少不对称极性生长而降低了种群的异质性。 LamA在其他生物中没有已知同源物，但在分枝杆菌物种中高度保守。我们发现LamA是分枝杆菌分裂复合体（“ divisome”）的成员。它抑制了新生的极点的生长，导致极地生长的不对称性。使用利福平和靶向细胞壁的药物，杀死缺乏lamA的单个细胞的动力学更加均匀和迅速。我们的结果表明，分枝杆菌编码的非保守蛋白可控制细胞生长模式，从而导致种群既异质又能更好地承受抗生素压力。

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  • 来源
    《Nature》 |2017年第7656期|153-157|共5页
  • 作者

    Rego E. Hesper; Audette Rebecca E.; Rubin Eric J.;

  • 作者单位

    Harvard TH Chan Sch Publ Hlth, Dept Immunol & Infect Dis, Boston, MA USA|Yale Univ, Sch Med, Dept Microbial Pathogenesis, New Haven, CT 06520 USA;

    Harvard TH Chan Sch Publ Hlth, Dept Immunol & Infect Dis, Boston, MA USA;

    Harvard TH Chan Sch Publ Hlth, Dept Immunol & Infect Dis, Boston, MA USA;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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