Toll-Like Receptor 3 Deficiency Leads to Altered Immune Responses to Chlamydia trachomatis Infection in Human Oviduct Epithelial Cells.
Toll-Like Receptor 3 Deficiency Leads to Altered Immune Responses to Chlamydia trachomatis Infection in Human Oviduct Epithelial Cells.
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Toll 样受体 3 缺陷会导致人输卵管上皮细胞对沙眼衣原体感染的免疫反应发生改变。
DOI：
10.1128/iai.00483-19
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发表时间：
2019
影响因子：
3.1
通讯作者：
Derbigny,WilbertA
中科院分区：
文献类型：
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作者：
Xu,JerryZ;Kumar,Ramesh;Gong,Haoli;Liu,Luyao;Ramos-Solis,Nicole;Li,Yujing;Derbigny,WilbertA
由沙眼衣原体感染引起的生殖道病变是全球性人类不育的重要原因。为了更好地理解与衣原体诱导的人类生殖道发病机制相关的机制，我们使用CRISPR基因组编辑来破坏人输卵管上皮（hOE）细胞系OE-E6/E7中的Toll样受体3（TLR 3）功能，以研究TLR 3信号传导在衣原体免疫应答中的可能作用。这些细胞中TLR 3功能的破坏显著减少了衣原体诱导的几种炎症生物标志物的合成，包括干扰素β（IFN-β），白细胞介素-6（IL-6），白细胞介素-6受体α（IL-6 R α），可溶性白细胞介素-6受体β（IL-6 R α），（sIL-6 R β或gpl 30）、IL-8、IL-20、IL-26、IL-34、可溶性肿瘤坏死因子受体1（sTNF-R1）、肿瘤坏死因子配体超家族成员13 B（TNFSF 13 B）、基质金属蛋白酶1（MMP-1）、MMP-2和MMP-3。相反，衣原体诱导的CCL 5、IL-29（IFN-λ1）和IL-28 A（IFN-λ2）的合成在TLR 3缺陷型hOE细胞中显著增加。我们的研究结果表明，TLR 3信号在限制生殖道纤维化，瘢痕形成和慢性炎症往往与人类衣原体疾病的作用。有趣的是，我们发现衣原体感染诱导hOE细胞产生与持久性、肿瘤转移和自身免疫相关的生物标志物，如可溶性CD 163（sCD 163）、几丁质酶-3样蛋白1、骨桥蛋白和正五聚蛋白-3;然而，它们的表达水平在TLR 3缺陷的hOE细胞中显著失调。最后，我们证明使用hOE细胞，TLR 3缺乏导致衣原体内的衣原体脂多糖（LPS）的量增加，这表明TLR 3缺乏导致衣原体复制增强，并可能增加人类感染时生殖道的发病机制。
Reproductive tract pathology caused by Chlamydia trachomatis infection is an important global cause of human infertility. To better understand the mechanisms associated withChlamydia-induced genital tract pathogenesis in humans, we used CRISPR genome editing to disrupt Toll-like receptor 3 (TLR3) function in the human oviduct epithelial (hOE) cell line OE-E6/E7 in order to investigate the possible role(s) of TLR3 signaling in the immune response toChlamydia. Disruption of TLR3 function in these cells significantly diminished theChlamydia-induced synthesis of several inflammation biomarkers, including interferon beta (IFN-β), interleukin-6 (IL-6), interleukin-6 receptor alpha (IL-6Rα), soluble interleukin-6 receptor beta (sIL-6Rβ, or gp130), IL-8, IL-20, IL-26, IL-34, soluble tumor necrosis factor receptor 1 (sTNF-R1), tumor necrosis factor ligand superfamily member 13B (TNFSF13B), matrix metalloproteinase 1 (MMP-1), MMP-2, and MMP-3. In contrast, theChlamydia-induced synthesis of CCL5, IL-29 (IFN-λ1), and IL-28A (IFN-λ2) was significantly increased in TLR3-deficient hOE cells compared to their wild-type counterparts. Our results indicate a role for TLR3 signaling in limiting the genital tract fibrosis, scarring, and chronic inflammation often associated with human chlamydial disease. Interestingly, we saw thatChlamydiainfection induced the production of biomarkers associated with persistence, tumor metastasis, and autoimmunity, such as soluble CD163 (sCD163), chitinase-3-like protein 1, osteopontin, and pentraxin-3, in hOE cells; however, their expression levels were significantly dysregulated in TLR3-deficient hOE cells. Finally, we demonstrate using hOE cells that TLR3 deficiency resulted in an increased amount of chlamydial lipopolysaccharide (LPS) withinChlamydiainclusions, which is suggestive that TLR3 deficiency leads to enhanced chlamydial replication and possibly increased genital tract pathogenesis during human infection.