Salmonella enteritidis Effector AvrA Stabilizes Intestinal Tight Junctions via the JNK Pathway
Salmonella enteritidis Effector AvrA Stabilizes Intestinal Tight Junctions via the JNK Pathway
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DOI：
10.1074/jbc.m116.757393
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发表时间：
2016-12-23
影响因子：
4.8
通讯作者：
Sun, Jun
中科院分区：
文献类型：
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作者：
Lin, Zhijie;Zhang, Yong-Guo;Sun, Jun
迄今为止，沙门氏菌致病机理的研究主要集中在鼠伤寒沙门氏菌上，而对第二种主要血清型沙门氏菌的致病机理知之甚少。沙门氏菌具有显示生物化学活性和调节宿主功能的效应蛋白。在此，我们在S.E-AvrA（-）中产生了效应子AvrA的缺失突变体，S. E-AvrA（-）和质粒介导的互补菌株S.E-AvrA（-）/pAvrA（+）（S.E-AvrA（+））。肠道。使用体外和体内感染模型，我们表明，AvrA稳定上皮紧密连接（TJ）蛋白，如ZO-1，在人肠上皮细胞。感染S.E-AvrA（+）的细胞的跨上皮电阻显著高于感染S.E-AvrA（-）的细胞。JNK通路的抑制抑制TJ蛋白的分解;我们发现，在野生型或S.E-AvrA（+）菌株感染的细胞中，拟南芥AvrA抑制JNK活性。因此，肠炎AvrA诱导的ZO-1稳定性是通过抑制JNK途径实现的。此外，S.E-AvrA（-）菌株在体外和体内均导致增强的细菌侵袭。综上所述，我们的数据揭示了AvrA在S.肠道：肠道AvrA稳定肠道TJ并减弱细菌入侵。在微生物-上皮相互作用中操纵JNK活性和TJ可能是治疗感染性疾病的新治疗方法。
Salmonella pathogenesis studies to date have focused on Salmonella typhimurium, and the pathogenesis of a second major serotype, Salmonella enteritidis, is poorly understood. Salmonella spp. possess effector proteins that display biochemical activities and modulate host functions. Here, we generated a deletion mutant of the effector AvrA, S.E-AvrA(-), and a plasmid-mediated complementary strain, S.E-AvrA(-)/pAvrA(+) (S.E-AvrA(+)), in S. Enteritidis. Using in vitro and in vivo infection models, we showed that AvrA stabilizes epithelial tight junction (TJ) proteins, such as ZO-1, in human intestinal epithelial cells. Transepithelial electrical resistance was significantly higher in cells infected with S.E-AvrA(+) than in cells infected with S.E-AvrA(-). Inhibition of the JNK pathway suppresses the disassembly of TJ proteins; we found that enteritidis AvrA inhibited JNK activity in cells infected with wild type or S.E-AvrA(+) strains. Therefore, Enteritidis AvrA-induced ZO-1 stability is achieved via suppression of the JNK pathway. Furthermore, the S.E-AvrA(-) strain led to enhanced bacterial invasion, both in vitro and in vivo. Taken together, our data reveal a novel role for AvrA in S. Enteritidis: Enteritidis AvrA stabilizes intestinal TJs and attenuates bacterial invasion. The manipulation of JNK activity and TJs in microbial-epithelial interactions may be a novel therapeutic approach for the treatment of infectious diseases.