Elevated Extracellular cGMP Produced after Exposure to Enterotoxigenic Escherichia coli Heat-Stable Toxin Induces Epithelial IL-33 Release and Alters Intestinal Immunity.
Elevated Extracellular cGMP Produced after Exposure to Enterotoxigenic Escherichia coli Heat-Stable Toxin Induces Epithelial IL-33 Release and Alters Intestinal Immunity.
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暴露于产肠毒素大肠杆菌后产生的细胞外cGMP升高热稳定毒素诱导上皮细胞IL-33释放并改变肠道免疫
DOI：
10.1128/iai.00707-20
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发表时间：
2021-03-17
影响因子：
3.1
通讯作者：
Bitoun JP
中科院分区：
文献类型：
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作者：
Motyka NI;Stewart SR;Hollifield IE;Kyllo TR;Mansfield JA;Norton EB;Clements JD;Bitoun JP
产肠毒素大肠杆菌（ETEC）是低收入至中等收入国家儿童中的主要肠道病原体。先前的研究将产热稳定肠毒素（ST）的ETEC确定为5岁以下儿童的流行性腹泻病原体。产肠毒素大肠杆菌（ETEC）是低收入至中等收入国家儿童中的主要肠道病原体。先前的研究将产热稳定肠毒素（ST）的ETEC确定为5岁以下儿童的流行性腹泻病原体。虽然许多研究已经评估了ETEC不耐热肠毒素（LT）与宿主上皮细胞和免疫的相互作用，但很少有研究尝试与ST进行类似的研究。为了进一步了解ST的发病机制，我们研究了ST对cGMP定位，上皮细胞细胞因子产生和免疫后抗体产生的影响。除了在磷酸二酯酶抑制剂（PDEis）存在下T84细胞中的稳健的细胞内cGMP（其防止环核苷酸的分解）之外，我们发现在存在或不存在PDEis的情况下，延长的ST中毒诱导细胞外cGMP积累。此外，ST中毒在小鼠体内诱导腔cGMP，表明分泌的cGMP可能具有其他细胞功能。使用转录组测序（RNA-seq）和定量PCR（qPCR），我们证明了ST中毒或临床使用的ST模拟利那洛肽治疗改变了炎症细胞因子基因表达，包括白细胞介素1（IL-1）家族成员IL-33，这也可以由细胞渗透性8-Br-cGMP诱导。最后，当在免疫过程中存在时，ST抑制针对特定抗原的抗体的诱导。总之，我们的研究表明，ST调节上皮细胞的生理和上皮和免疫室之间的相互作用。
Enterotoxigenic Escherichia coli (ETEC) is a major diarrheal pathogen in children in low- to middle-income countries. Previous studies identified heat-stable enterotoxin (ST)-producing ETEC as a prevalent diarrheal pathogen in children younger than 5 years. Enterotoxigenic Escherichia coli (ETEC) is a major diarrheal pathogen in children in low- to middle-income countries. Previous studies identified heat-stable enterotoxin (ST)-producing ETEC as a prevalent diarrheal pathogen in children younger than 5 years. While many studies have evaluated the interaction of ETEC heat-labile enterotoxin (LT) with host epithelium and immunity, few investigations have attempted similar studies with ST. To further understand ST pathogenesis, we examined the impact of ST on cGMP localization, epithelial cell cytokine production, and antibody development following immunization. In addition to robust intracellular cGMP in T84 cells in the presence of phosphodiesterase inhibitors (PDEis) that prevent the breakdown of cyclic nucleotides, we found that prolonged ST intoxication induced extracellular cGMP accumulation in the presence or absence of PDEis. Further, ST intoxication induced luminal cGMP in vivo in mice, suggesting that secreted cGMP may have other cellular functions. Using transcriptome sequencing (RNA-seq) and quantitative PCR (qPCR), we demonstrated that ST intoxication, or treatment with the clinically used ST mimic linaclotide, altered inflammatory cytokine gene expression, including the interleukin 1 (IL-1) family member IL-33, which could also be induced by cell-permeative 8-Br-cGMP. Finally, when present during immunization, ST suppressed induction of antibodies to specific antigens. In conclusion, our studies indicate that ST modulates epithelial cell physiology and the interplay between the epithelial and immune compartments.