Analysis of the Human Mucosal Response to Cholera Reveals Sustained Activation of Innate Immune Signaling Pathways
Analysis of the Human Mucosal Response to Cholera Reveals Sustained Activation of Innate Immune Signaling Pathways
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DOI：
10.1128/iai.00594-17
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发表时间：
2018-02-01
影响因子：
3.1
通讯作者：
Harris, Jason B.
中科院分区：
文献类型：
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作者：
Bourque, Daniel L.;Bhuiyan, Taufiqur Rahman;Harris, Jason B.
为了更好地了解对霍乱弧菌感染的先天免疫反应，我们使用补液后立即和30天和180天后获得的活检标本，追踪了11名孟加拉国霍乱成人十二指肠黏膜中的基因表达。我们确定了差异表达的基因，并进行了分析，以预测差异调控途径和上游调控因子。在急性霍乱期间，与先天免疫相关的基因表达广泛增加，包括NF-kappa B、丝裂原活化蛋白激酶（MAPK）和toll样受体（TLR）介导的信号通路的激活，出乎意料的是，这种情况在感染后甚至持续30天。关注基因表达的早期差异，我们在11名参与者中确定了37个基因在第2天和第30天的差异表达。这些基因包括在固有层细胞中表达的内体toll样受体基因TLR8。强调体内内体tlr介导的信号通路的潜在作用，我们的途径分析发现干扰素调节因子7和β 1和α 2干扰素是霍乱期间激活的上游调节因子。在先天免疫效应物中，我们发现DUOX2基因（一种NADPH氧化酶，参与维持肠道内稳态）在霍乱期间在肠上皮细胞中上调。值得注意的是，当Caco-2或THP-1细胞分别被活霍乱弧菌刺激而不是单独被热杀灭的生物体或霍乱毒素刺激时，DUOX2和TLR8表达的增加也在体外模拟。这些对霍乱弧菌的先天免疫反应的先前未确定的特征扩展了我们对霍乱后体内激活的粘膜免疫信号通路和效应物的理解。
To better understand the innate immune response to Vibrio cholerae infection, we tracked gene expression in the duodenal mucosa of 11 Bangladeshi adults with cholera, using biopsy specimens obtained immediately after rehydration and 30 and 180 days later. We identified differentially expressed genes and performed an analysis to predict differentially regulated pathways and upstream regulators. During acute cholera, there was a broad increase in the expression of genes associated with innate immunity, including activation of the NF-kappa B, mitogen-activated protein kinase (MAPK), and Toll-like receptor (TLR)-mediated signaling pathways, which, unexpectedly, persisted even 30 days after infection. Focusing on early differences in gene expression, we identified 37 genes that were differentially expressed on days 2 and 30 across the 11 participants. These genes included the endosomal Toll-like receptor gene TLR8, which was expressed in lamina propria cells. Underscoring a potential role for endosomal TLR-mediated signaling in vivo, our pathway analysis found that interferon regulatory factor 7 and beta 1 and alpha 2 interferons were among the top upstream regulators activated during cholera. Among the innate immune effectors, we found that the gene for DUOX2, an NADPH oxidase involved in the maintenance of intestinal homeostasis, was upregulated in intestinal epithelial cells during cholera. Notably, the observed increases in DUOX2 and TLR8 expression were also modeled in vitro when Caco-2 or THP-1 cells, respectively, were stimulated with live V. cholerae but not with heat-killed organisms or cholera toxin alone. These previously unidentified features of the innate immune response to V. cholerae extend our understanding of the mucosal immune signaling pathways and effectors activated in vivo following cholera.