LadS is a calcium-responsive kinase that induces acute-to-chronic virulence switch in Pseudomonas aeruginosa
LadS is a calcium-responsive kinase that induces acute-to-chronic virulence switch in Pseudomonas aeruginosa
复制标题
DOI：
10.1038/nmicrobiol.2016.184
复制
发表时间：
2017-01-01
影响因子：
28.3
通讯作者：
Jenal, Urs
中科院分区：
文献类型：
--
作者：
Broder, Ursula N.;Jaeger, Tina;Jenal, Urs
致病菌的毒力是一个严格控制的过程，以促进入侵和生存在宿主组织。虽然控制毒力的途径已被详细定义，但调节这些过程的信号却知之甚少。机会致病菌铜绿假单胞菌引起人类急性和慢性感染。疾病进展通常与急性毒力的丧失以及生物膜和慢性行为的出现相关。急性至慢性的转换由全局Gac/Rsm途径控制。使用一个新开发的急性-慢性双报告系统，我们表明，钙刺激的GAC/RSM途径，通过GAC相关的杂合组氨酸激酶LadS。我们发现，钙结合到周质DISMED 2传感器结构域的LadS激活其激酶活性。钙激活Gac/Rsm途径导致向慢性程序的转换，并通过降低铜绿假单胞菌生长速率赋予药物耐受性。来自囊性纤维化气道的临床分离株在慢性感染期间保持其钙反应。我们的数据表明，钙感应进化为适应铜绿假单胞菌的机会主义生活方式，钙作为宿主信号，以平衡急性至慢性感染期间的行为。在宿主-病原体相互作用中建立钙信号传导增加了越来越多的证据，表明钙在细菌信号传导中的关键作用。
Virulence of pathogenic bacteria is a tightly controlled process to facilitate invasion and survival in host tissues. Although pathways controlling virulence have been defined in detail, signals modulating these processes are poorly understood. The opportunistic pathogen Pseudomonas aeruginosa causes acute and chronic infections in humans. Disease progression is typically associated with a loss of acute virulence and the emergence of biofilms and chronic behaviour. The acute-to-chronic switch is governed by the global Gac/Rsm pathway. Using a newly developed acute-chronic dual reporter system we show that calcium stimulates the Gac/Rsm pathway via the Gac-associated hybrid histidine kinase LadS. We show that calcium binds to the periplasmic DISMED2 sensor domain of LadS to activate its kinase activity. Activation of the Gac/Rsm pathway by calcium leads to a switch to the chronic program and confers drug tolerance by reducing P. aeruginosa growth rate. Clinical isolates from cystic fibrosis airways retain their calcium response during chronic infections. Our data imply that calcium sensing evolved as an adaptation to the opportunistic lifestyle of P. aeruginosa and that calcium serves as a host signal to balance acute-to-chronic behaviour during infections. Establishing calcium signalling in host-pathogen interaction adds to growing evidence indicating key roles for calcium in bacterial signalling.