Dysregulation of Escherichia coli α-hemolysin expression alters the course of acute and persistent urinary tract infection
Dysregulation of Escherichia coli α-hemolysin expression alters the course of acute and persistent urinary tract infection
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DOI：
10.1073/pnas.1500374112
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发表时间：
2015-02-24
影响因子：
11.1
通讯作者：
Hultgren, Scott J.
中科院分区：
文献类型：
--
作者：
Nagamatsu, Kanna;Hannan, Thomas J.;Hultgren, Scott J.
尿路感染（UTI）是最常见的细菌感染之一，在女性中引起相当大的发病率。尽管进行了适当的抗生素治疗，感染仍高度复发。尿路致病性大肠杆菌（UPEC）是尿路感染最常见的病原体，它侵入膀胱上皮细胞（BEC）并形成克隆性细胞内细菌群落（IBC）。成熟后，IBC分散，细菌扩散到邻近的BEC重复这个循环。这一过程使UPEC在面对先天防御机制（包括排尿、上皮脱落和多形核白细胞的流入）时获得立足点。在这里，我们调查的机制和动力学尿路上皮脱落在感染的早期急性阶段。我们表明，UPEC α-溶血素（HlyA）诱导Caspase-1/Caspase-4依赖性炎症细胞死亡的人尿路上皮细胞，我们证明，反应调节（CpxR）-传感器激酶（CpxA）的双组分系统（CpxRA），调节毒力基因的表达，响应于环境信号，是微调HlyA细胞毒性的关键。cpxR转录反应调节因子的缺失解除了hlyA表达的抑制，导致人尿路上皮细胞中Caspase-1/Caspase-4-和NOD样受体家族、含有pyrin结构域的3-依赖性炎性细胞死亡增强。在体内，HlyA在急性膀胱感染期间的过表达诱导更快速和广泛的剥脱和减少的膀胱细菌负荷。通过抑制胱天蛋白酶-1和胱天蛋白酶-11（胱天蛋白酶-4的鼠同系物）完全恢复膀胱适应性。因此，我们已经发现，通过CpxRA系统微调HlyA表达对于增强膀胱中的UPEC适应性至关重要。这些结果对我们理解UPEC如何建立持久的殖民化具有重要意义。
Urinary tract infections (UTIs) are among the most common bacterial infections, causing considerable morbidity in females. Infection is highly recurrent despite appropriate antibiotic treatment. Uropathogenic Escherichia coli (UPEC), the most common causative agent of UTIs, invades bladder epithelial cells (BECs) and develops into clonal intracellular bacterial communities (IBCs). Upon maturation, IBCs disperse, with bacteria spreading to neighboring BECs to repeat this cycle. This process allows UPEC to gain a foothold in the face of innate defense mechanisms, including micturition, epithelial exfoliation, and the influx of polymorphonuclear leukocytes. Here, we investigated the mechanism and dynamics of urothelial exfoliation in the early acute stages of infection. We show that UPEC a-hemolysin (HlyA) induces Caspase-1/Caspase-4-dependent inflammatory cell death in human urothelial cells, and we demonstrate that the response regulator (CpxR)-sensor kinase (CpxA) two-component system (CpxRA), which regulates virulence gene expression in response to environmental signals, is critical for fine-tuning HlyA cytotoxicity. Deletion of the cpxR transcriptional response regulator derepresses hlyA expression, leading to enhanced Caspase-1/Caspase-4- and NOD-like receptor family, pyrin domain containing 3-dependent inflammatory cell death in human urothelial cells. In vivo, overexpression of HlyA during acute bladder infection induces more rapid and extensive exfoliation and reduced bladder bacterial burdens. Bladder fitness is restored fully by inhibition of Caspase-1 and Caspase-11, the murine homolog of Caspase-4. Thus, we have discovered that fine-tuning of HlyA expression by the CpxRA system is critical for enhancing UPEC fitness in the urinary bladder. These results have significant implications for our understanding of how UPEC establishes persistent colonization.