A Bacterial Inflammation Sensor Regulates c-di-GMP Signaling, Adhesion, and Biofilm Formation.
A Bacterial Inflammation Sensor Regulates c-di-GMP Signaling, Adhesion, and Biofilm Formation.
复制标题
DOI：
10.1128/mbio.00173-21
复制
发表时间：
2021-06-29
期刊：
影响因子：
6.4
通讯作者：
Guillemin K
中科院分区：
文献类型：
--
作者：
Perkins A;Tudorica DA;Teixeira RD;Schirmer T;Zumwalt L;Ogba OM;Cassidy CK;Stansfeld PJ;Guillemin K
定植于动物的细菌必须克服或与炎症产生的活性氧产物共存，炎症是先天免疫的前线防御。其中包括中性粒细胞氧化剂漂白剂次氯酸 (HOCl)，它是一种有效的抗菌剂，通过蛋白质、脂质和 DNA 的非特异性氧化来杀死细菌。在这里，我们报告说，为了响应 HOCl 水平的增加，大肠杆菌通过激活二鸟苷酸环化酶 DgcZ 来调节生物膜的产生。我们确定 DgcZ 传感 HOCl 的机制是直接氧化其调节化学感受器锌结合 (CZB) 结构域。对 CZB 信号转导的剖析表明，保守的锌结合半胱氨酸的氧化控制 CZB Zn2+ 占据，进而调节相关 GGDEF 结构域对 c-di-GMP 的催化作用。我们发现 DgcZ 依赖性生物膜形成和 HOCl 传感在体内受到保守的锌配位半胱氨酸的调节。此外，模拟氧化 CZB 状态的点突变体会增加生物膜总量。对细菌基因组的调查表明，许多操纵宿主炎症作为其定植策略一部分的病原菌都拥有 CZB 调节的二鸟苷酸环化酶和化学感受器。我们的研究结果表明，CZB 结构域是锌敏感调节因子，允许宿主相关细菌通过与 HOCl 的反应来感知宿主炎症。
Bacteria that colonize animals must overcome, or coexist, with the reactive oxygen species products of inflammation, a front-line defense of innate immunity. Among these is the neutrophilic oxidant bleach, hypochlorous acid (HOCl), a potent antimicrobial that plays a primary role in killing bacteria through nonspecific oxidation of proteins, lipids, and DNA. Here, we report that in response to increasing HOCl levels, Escherichia coli regulates biofilm production via activation of the diguanylate cyclase DgcZ. We identify the mechanism of DgcZ sensing of HOCl to be direct oxidation of its regulatory chemoreceptor zinc-binding (CZB) domain. Dissection of CZB signal transduction reveals that oxidation of the conserved zinc-binding cysteine controls CZB Zn2+ occupancy, which in turn regulates the catalysis of c-di-GMP by the associated GGDEF domain. We find DgcZ-dependent biofilm formation and HOCl sensing to be regulated in vivo by the conserved zinc-coordinating cysteine. Additionally, point mutants that mimic oxidized CZB states increase total biofilm. A survey of bacterial genomes reveals that many pathogenic bacteria that manipulate host inflammation as part of their colonization strategy possess CZB-regulated diguanylate cyclases and chemoreceptors. Our findings suggest that CZB domains are zinc-sensitive regulators that allow host-associated bacteria to perceive host inflammation through reactivity with HOCl.