Decreased SLC26A3 expression and function in intestinal epithelial cells in response to Cryptosporidium parvum infection
Decreased SLC26A3 expression and function in intestinal epithelial cells in response to Cryptosporidium parvum infection
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DOI：
10.1152/ajpcell.00278.2019
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发表时间：
2019-12-01
影响因子：
5.5
通讯作者：
Dudeja, Pradeep K.
中科院分区：
文献类型：
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作者：
Kumar, Anoop;Jayawardena, Dulari;Dudeja, Pradeep K.
原生动物寄生虫微小隐孢子虫（CP）会引起隐孢子虫病，这是一种世界范围内的腹泻疾病。免疫活性宿主的感染通常导致急性、自限性或复发性腹泻。然而，在免疫功能低下的个体中，感染可引起暴发性腹泻、肠外表现和死亡。迄今为止，CP诱导的结肠炎发病机制还不清楚。腹泻疾病最常见的涉及液体和电解质的分泌增加和/或吸收减少。我们和其他人先前已经表明，由于SLC 26 A3的失调[在腺瘤中下调（P26 A3）]，感染性腹泻中的氯吸收受损。人小肠顶端膜Cl-/HCO 3-交换蛋白。然而.还没有关于CP感染对细菌活性影响的研究。因此，我们在体外和体内研究了CP感染后肠上皮细胞中的表达和功能。Caco-2细胞单层的CP感染（24孔板中0.5 x 10（6）个卵囊/孔，24 h）显著降低Cl-/HCO 3-交换活性（以DIDS敏感性I-125摄取量测量）以及Caco-2 mRNA和蛋白水平。在离体小鼠肠源性单层和体内C57 BL/6小鼠回肠和空肠粘膜中CP感染24 h后，也观察到C57 BL/6 mRNA和蛋白质的显著下调。然而，在体内感染后48 h，对p53 mRNA和蛋白的影响减弱，在感染后5天，p53恢复到正常水平。我们的研究结果表明，受损的氯化物吸收由于下调的CPG可能是一个促成因素CP诱导的急性，自限性腹泻的免疫功能正常的主机。
The protozoan parasite Cryptosporidium parvum (CP) causes cryptosporidiosis, a diarrheal disease worldwide. Infection in immunocompetent hosts typically results in acute, self-limiting, or recurrent diarrhea. However, in immunocompromised individuals infection can cause fulminant diarrhea, extraintestinal manifestations, and death. To date, the mechanisms underlying CP-induced diarrheal pathogenesis are poorly understood. Diarrheal diseases most commonly involve increased secretion and/or decreased absorption of fluid and electrolytes. We and others have previously shown impaired chloride absorption in infectious diarrhea due to dysregulation of SLC26A3 [downregulated in adenoma (DRA)]. the human intestinal apical membrane Cl-/HCO3- exchanger protein. However. there are no studies on the effects of CP infection on DRA activity. Therefore, we examined the expression and function of DRA in intestinal epithelial cells in response to CP infection in vitro and in vivo. CP infection (0.5 x 10(6) oocysts/well in 24-well plates, 24 h) of Caco-2 cell monolayers significantly decreased Cl-/HCO3- exchange activity (measured as DIDS-sensitive I-125 uptake) as well as DRA mRNA and protein levels. Substantial downregulation of DRA mRNA and protein was also observed following CP infection ex vivo in mouse enteroid-derived monolayers and in vivo in the ileal and jejunal mucosa of C57BL/6 mice for 24 h. However, at 48 h after infection in vivo, the effects on DRA mRNA and protein were attenuated and at 5 days after infection DRA returned to normal levels. Our results suggest that impaired chloride absorption due to downregulation of DRA could be one of the contributing factors to CP-induced acute, self-limiting diarrhea in immunocompetent hosts.