Bacterial virulence factor inhibits caspase-4/11 activation in intestinal epithelial cells.
Bacterial virulence factor inhibits caspase-4/11 activation in intestinal epithelial cells.
复制标题
作者：
人类致病性大肠杆菌(EPEC)和鼠类病原菌轮状柠檬酸杆菌(Citrobacter Rolinum)通过附着和消除病变形成而定植于肠粘膜，引起腹泻疾病。EPEC和轮状芽胞杆菌III型分泌系统(T3SS)效应器抑制先天免疫反应和免疫细胞的渗透。炎症性caspase如caspase-1和caspase-4/11通过其处理IL-1、β和IL-18等细胞因子的能力，是肠道内宿主防御和炎症的重要介质。在此，我们报道了效应子NleF结合caspase-4的催化结构域并抑制其蛋白分解活性。肠上皮细胞(IECS)感染后，EPEC以NleF依赖的方式抑制caspase-4和IL-18的加工。IECs中Caspase-4的缺失阻止了成熟IL-18的分泌，以应对EPEC∆nleF的感染。NleF依赖的对小鼠结肠caspase-11的抑制可阻止IL-18的分泌和中性粒细胞在新月形虫感染早期的流入。野生型轮状拟青霉和轮状拟青霉∆nleF均不能引起CAS11或CASP1/11缺陷小鼠中性粒细胞的浸润和IL-18的分泌。因此，IECS通过caspase-4/11-IL-18轴在调节肠道早期先天免疫反应中发挥关键作用，该轴是肠道病原体编码的毒力因子的靶标。
The human pathogen enteropathogenic Escherichia coli (EPEC), as well as the mouse pathogen Citrobacter rodentium, colonize the gut mucosa via attaching and effacing lesion formation and cause diarrheal diseases. EPEC and C. rodentium type III secretion system (T3SS) effectors repress innate immune responses and infiltration of immune cells. Inflammatory caspases such as caspase-1 and caspase-4/11 are crucial mediators of host defense and inflammation in the gut via their ability to process cytokines such as IL-1β and IL-18. Here we report that the effector NleF binds the catalytic domain of caspase-4 and inhibits its proteolytic activity. Following infection of intestinal epithelial cells (IECs) EPEC inhibited caspase-4 and IL-18 processing in an NleF-dependent manner. Depletion of caspase-4 in IECs prevented the secretion of mature IL-18 in response to infection with EPEC∆nleF. NleF-dependent inhibition of caspase-11 in colons of mice prevented IL-18 secretion and neutrophil influx at early stages of C. rodentium infection. Neither wild-type C. rodentium nor C. rodentium∆nleF triggered neutrophil infiltration or IL-18 secretion in Cas11 or Casp1/11 deficient mice. Thus, IECs play a key role in modulating early innate immune responses in the gut via a caspase-4/11 - IL-18 axis, which is targeted by virulence factors encoded by enteric pathogens.
登录
查看更多内容
影响因子：
32.4
作者：
Basu R;O'Quinn DB;Silberger DJ;Schoeb TR;Fouser L;Ouyang W;Hatton RD;Weaver CT
通讯作者：
Weaver CT
NLRC4在肠上皮细胞中的表达介导了针对肠道病原体的保护。
影响因子：
8
作者：
通讯作者：
--
影响因子：
4.8
作者：
Liu, Zhiping;Zaki, Md Hasan;Kanneganti, Thirumala-Devi
通讯作者：
Kanneganti, Thirumala-Devi
DOI：
10.1073/pnas.0911609106
发表时间：
2010-02-16
影响因子：
11.1
作者：
Hemrajani, Cordula;Berger, Cedric N.;Frankel, Gad
通讯作者：
Frankel, Gad
DOI：
10.1126/science.1240988
发表时间：
2013-09-13
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Hagar JA;Powell DA;Aachoui Y;Ernst RK;Miao EA
通讯作者：
Miao EA