Stochastic activation of a family of TetR type transcriptional regulators controls phenotypic heterogeneity in Acinetobacter baumannii.
Stochastic activation of a family of TetR type transcriptional regulators controls phenotypic heterogeneity in Acinetobacter baumannii.
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DOI：
10.1093/pnasnexus/pgac231
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发表时间：
2022-11
期刊：
影响因子：
--
通讯作者：
Rather, Philip N.
中科院分区：
文献类型：
--
作者：
Perez-Varela, Maria;Tierney, Aimee R. P.;Dawson, Emma;Hutcheson, Anna R.;Tipton, Kyle A.;Anderson, Sarah E.;Haldopoulos, Marina E.;Song, Shaina;Tomlinson, Brooke R.;Shaw, Lindsey N.;Weiss, David S.;Kim, Minsu;Rather, Philip N.
表型异质性是调节细菌毒力的重要机制，其中单个调节开关通常被激活以产生毒性和无毒力亚群。条件致病菌鲍氏不动杆菌可以在毒性不透明（VIR-O）和无毒力半透明亚群之间高频率转换，通过形成不透明或半透明菌落的细胞来区分。我们证明了11 TetR型转录调节因子（TTTR）的表达可以将细胞从VIR-O不透明亚群驱动到形成半透明集落的细胞。值得注意的是，在VIR-O细胞亚群中，这些TTTR中的四个以不同的组合被随机激活，以驱动细胞进入半透明状态。所得半透明亚变体表现出独特的表型差异，并且大多数是无毒的。由于它们的功能冗余，需要所有四个TTTR失活的四重突变体来观察从VIR-O状态转换的损失。此外，我们证明了一个小RNA，SrvS，作为一个“变阻器”，其中SrvS的表达水平影响两个VIR-O半透明的开关频率，TTTR被激活时，VIR-O细胞开关。总之，这项工作揭示了细菌表型转换的新范式，其中前所未有数量的相关转录调节因子以不同的组合被激活，以控制毒力并产生具有独特表型特性的独特半透明亚变体。
Phenotypic heterogeneity is an important mechanism for regulating bacterial virulence, where a single regulatory switch is typically activated to generate virulent and avirulent subpopulations. The opportunistic pathogen Acinetobacter baumannii can transition at high frequency between virulent opaque (VIR-O) and avirulent translucent subpopulations, distinguished by cells that form opaque or translucent colonies. We demonstrate that expression of 11 TetR-type transcriptional regulators (TTTRs) can drive cells from the VIR-O opaque subpopulation to cells that form translucent colonies. Remarkably, in a subpopulation of VIR-O cells, four of these TTTRs were stochastically activated in different combinations to drive cells to the translucent state. The resulting translucent subvariants exhibited unique phenotypic differences and the majority were avirulent. Due to their functional redundancy, a quadruple mutant with all four of these TTTRs inactivated was required to observe a loss of switching from the VIR-O state. Further, we demonstrate a small RNA, SrvS, acts as a “rheostat,” where the levels of SrvS expression influences both the VIR-O to translucent switching frequency, and which TTTR is activated when VIR-O cells switch. In summary, this work has revealed a new paradigm for phenotypic switching in bacteria, where an unprecedented number of related transcriptional regulators are activated in different combinations to control virulence and generate unique translucent subvariants with distinct phenotypic properties.
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影响因子：
6.4
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