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首页> 外文期刊>Journal of Parasitology >TLR4 promotes Cryptosporidium parvum clearance in a mouse model of biliary cryptosporidiosis.
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TLR4 promotes Cryptosporidium parvum clearance in a mouse model of biliary cryptosporidiosis.

机译：TLR4促进胆囊隐孢子虫病小鼠模型中的小隐孢子虫清除。

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Cholangiocytes, the epithelial cells lining intrahepatic bile ducts, express multiple toll-like receptors (TLRs) and, thus, have the capacity to recognize and respond to microbial pathogens. In previous work, we demonstrated that TLR4, which is activated by gram-negative lipopolysaccharide (LPS), is upregulated in cholangiocytes in response to infection with Cryptosporidium parvum in vitro and contributes to nuclear factor-kappaB (NF-kB) activation. Here, using an in vivo model of biliary cryptosporidiosis, we addressed the functional role of TLR4 in C. parvum infection dynamics and hepatobiliary pathophysiology. We observed that C57BL mice clear the infection by 3 wk post-infection (PI). In contrast, parasites were detected in bile and stool in TLR4-deficient mice at 4 wk PI. The liver enzymes alanine transaminase (ALT) and aspartate transaminase (AST), and the proinflammatory cytokines tumor necrosis factor (TNF)- alpha , interferon (IFN)- gamma , and interleukin (IL)-6 peaked at 1 to 2 wk PI and normalized by 4 wk in infected C57BL mice. C57BL mice also demonstrated increased cholangiocyte proliferation (PCNA staining) at 1 wk PI that was resolved by 2 wk PI. In contrast, TLR4-deficient mice showed persistently elevated serum ALT and AST, elevated hepatic IL-6 levels, and histological evidence of hepatocyte necrosis, increased inflammatory cell infiltration, and cholangiocyte proliferation through 4 wk PI. These data suggest that a TLR4-mediated response is required for efficient eradication of biliary C. parvum infection in vivo, and lack of this pattern-recognition receptor contributes to an altered inflammatory response and an increase in hepatobiliary pathology.
机译：胆管细胞（位于肝内胆管内的上皮细胞）表达多种toll样受体（TLR），因此具有识别和应对微生物病原体的能力。在先前的工作中，我们证明了革兰氏阴性脂多糖（LPS）激活的TLR4在胆管细胞中被上皮小隐隐孢子虫感染的反应上调，并有助于核因子-κB（NF -kB）激活。在这里，我们使用胆囊隐孢子虫病的体内模型，研究了TLR4在iC中的功能。小病毒感染动力学和肝胆病理生理学。我们观察到C57BL小鼠在感染后3周（PI）清除了感染。相反，在4 wk PI时，在TLR4缺陷型小鼠的胆汁和粪便中检测到了寄生虫。肝酶丙氨酸转氨酶（ALT）和天冬氨酸转氨酶（AST）以及促炎性细胞因子肿瘤坏死因子（TNF）-α，干扰素（IFN）-γ和白介素（IL）-6在PI的1至2周达到峰值，在受感染的C57BL小鼠中以4周标准化。 C57BL小鼠还表现出在1 wk PI时胆管细胞增殖增加（PCNA染色），而2 wk PI可以解决。相比之下，TLR4缺陷小鼠表现出持续升高的血清ALT和AST，升高的肝IL-6水平以及通过4 wk PI肝细胞坏死，炎性细胞浸润增加和胆管细胞增殖的组织学证据。这些数据表明，TLR4介导的反应是有效消除胆汁C所必需的。体内小病毒感染和缺乏这种模式识别受体会导致炎症反应改变和肝胆病理改变。

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