Cyclic di-GMP Modulates Gene Expression in Lyme Disease Spirochetes at the Tick-Mammal Interface To Promote Spirochete Survival during the Blood Meal and Tick-to-Mammal Transmission
Cyclic di-GMP Modulates Gene Expression in Lyme Disease Spirochetes at the Tick-Mammal Interface To Promote Spirochete Survival during the Blood Meal and Tick-to-Mammal Transmission
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DOI：
10.1128/iai.00315-15
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发表时间：
2015-08-01
影响因子：
3.1
通讯作者：
Radolf, Justin D.
中科院分区：
文献类型：
--
作者：
Caimano, Melissa J.;Dunham-Ems, Star;Radolf, Justin D.
莱姆病螺旋体（Borrelia burgdorferi）主要通过Hk 1/Rrp 1双组分系统（TCS）和Rrp 2/RpoN/RpoS途径将环境感知和基因调控偶联。从收购开始，我们重新评估了这些途径的贡献，螺旋体的生存和基因调控在整个地方性流行病周期。B的实时成像。burgdorferi在被捕获的行为中揭示了RpoS的缺乏和随后的滴答期基因的去阻遏赋予了中肠定殖所需的Stay信号。除了Rpos关闭状态引起的行为变化外，获得需要通过Hk 1/Rrp 1 TCS激活环状二-GMP（c-di-GMP）合成; B。缺乏任何一种成分的伯氏螺旋体在血餐期间被破坏。先前的研究将这种引人注目的表型归因于甘油摄取和利用减少引起的代谢病变。然而，在头对头的比较中，B. burgdorferi Delta glp突变体比B具有显著更大的在蜱喂养中存活的能力。burgdorferi Delta hk 1或Delta rrp 1突变体，明确地确定甘油代谢只是c-di-GMP提供的保护的一个组成部分。本文提供的数据表明，由c-di-GMP介导的保护性反应是多因素的，涉及趋化反应，利用替代底物产生能量和中间代谢，以及重塑细胞包膜作为防御螺旋体对抗血餐期间产生的威胁的手段。通过地方流行病周期的c-di-GMP调控基因的表达谱支持我们的论点，即Hk 1/Rrp 1 TCS的功能主要是，如果不是排他的，在蜱。这些数据还提出了c-di-GMP在若虫传播过程中增强Rpos依赖基因亚组表达的可能性。
Borrelia burgdorferi, the Lyme disease spirochete, couples environmental sensing and gene regulation primarily via the Hk1/Rrp1 two-component system (TCS) and Rrp2/RpoN/RpoS pathways. Beginning with acquisition, we reevaluated the contribution of these pathways to spirochete survival and gene regulation throughout the enzootic cycle. Live imaging of B. burgdorferi caught in the act of being acquired revealed that the absence of RpoS and the consequent derepression of tick-phase genes impart a Stay signal required for midgut colonization. In addition to the behavioral changes brought on by the RpoS-off state, acquisition requires activation of cyclic di-GMP (c-di-GMP) synthesis by the Hk1/Rrp1 TCS; B. burgdorferi lacking either component is destroyed during the blood meal. Prior studies attributed this dramatic phenotype to a metabolic lesion stemming from reduced glycerol uptake and utilization. In a head-to-head comparison, however, the B. burgdorferi Delta glp mutant had a markedly greater capacity to survive tick feeding than B. burgdorferi Delta hk1 or Delta rrp1 mutants, establishing unequivocally that glycerol metabolism is only one component of the protection afforded by c-di-GMP. Data presented herein suggest that the protective response mediated by c-di-GMP is multifactorial, involving chemotactic responses, utilization of alternate substrates for energy generation and intermediary metabolism, and remodeling of the cell envelope as a means of defending spirochetes against threats engendered during the blood meal. Expression profiling of c-di-GMP-regulated genes through the enzootic cycle supports our contention that the Hk1/Rrp1 TCS functions primarily, if not exclusively, in ticks. These data also raise the possibility that c-di-GMP enhances the expression of a subset of RpoS-dependent genes during nymphal transmission.