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Mechanisms of Maintenance of Foot-and-Mouth Disease Virus Persistence Inferred From Genes Differentially Expressed in Nasopharyngeal Epithelia of Virus Carriers and Non-carriers.
Frontiers in Veterinary Science ( IF 2.6 ) Pub Date : 2020-05-15 , DOI: 10.3389/fvets.2020.00340
James J Zhu 1 , Carolina Stenfeldt 1, 2 , Elizabeth A Bishop 1 , Jessica A Canter 1, 3 , Michael Eschbaumer 4 , Luis L Rodriguez 1 , Jonathan Arzt 1
Affiliation  

Foot-and-mouth disease virus (FMDV) causes persistent infection of nasopharyngeal epithelial cells in ~50% of infected ruminants. The mechanisms involved are not clear. This study provides a continued investigation of differentially expressed genes (DEG) identified in a previously published transcriptomic study analyzing micro-dissected epithelial samples from FMDV carriers and non-carriers. Pathway analysis of DEG indicated that immune cell trafficking, cell death and hematological system could be affected by the differential gene expression. Further examination of the DEG identified five downregulated (chemerin, CCL23, CXCL15, CXCL16, and CXCL17) and one upregulated (CCL2) chemokines in carriers compared to non-carriers. The differential expression could reduce the recruitment of neutrophils, antigen-experienced T cells and dendritic cells and increase the migration of macrophages and NK cells to the epithelia in carriers, which was supported by DEG expressed in these immune cells. Downregulated chemokine expression could be mainly due to the inhibition of canonical NFκB signaling based on DEG in the signaling pathways and transcription factor binding sites predicted from the proximal promoters. Additionally, upregulated CD69, IL33, and NID1 and downregulated CASP3, IL17RA, NCR3LG1, TP53BP1, TRAF3, and TRAF6 in carriers could inhibit the Th17 response, NK cell cytotoxicity and apoptosis. Based on our findings, we hypothesize that (1) under-expression of chemokines that recruit neutrophils, antigen-experienced T cells and dendritic cells, (2) blocking NK cell binding to target cells and (3) suppression of apoptosis induced by death receptor signaling, viral RNA, and cell-mediated cytotoxicity in the epithelia compromised virus clearance and allowed FMDV to persist. These hypothesized mechanisms provide novel information for further investigation of persistent FMDV infection.



中文翻译:

从携带者和非携带者的鼻咽上皮细胞中差异表达的基因推断出口蹄疫病毒持续存在的维持机制。

口蹄疫病毒(FMDV)导致约50%的反刍动物持续感染鼻咽上皮细胞。涉及的机制尚不清楚。这项研究提供了对以前发表的转录组研究中鉴定的差异表达基因(DEG)的持续研究,该研究分析了来自FMDV携带者和非携带者的微解剖上皮样品。DEG的通路分析表明,差异基因表达可能会影响免疫细胞的运输,细胞死亡和血液系统。与非载体相比,对DEG的进一步检查发现载体中有5种下调的趋化因子(chemerin,CCL23,CXCL15,CXCL16和CXCL17)和一种上调的(CCL2)趋化因子。差异表达可以减少中性粒细胞的募集,抗原经历过的T细胞和树突状细胞,并增加巨噬细胞和NK细胞向载体上皮的迁移,这由这些免疫细胞中表达的DEG支持。趋化因子表达下调可能主要是由于基于DEG的经典NFκB信号在信号通路和近端启动子预测的转录因子结合位点的抑制。此外,载体中CD69,IL33和NID1的上调以及CASP3,IL17RA,NCR3LG1,TP53BP1,TRAF3和TRAF6的下调可以抑制Th17反应,NK细胞毒性和凋亡。根据我们的发现,我们假设(1)趋化因子的表达不足,这些趋化因子募集嗜中性粒细胞,抗原经历过的T细胞和树突状细胞,(2)阻断NK细胞与靶细胞的结合,以及(3)抑制死亡受体信号传导,病毒RNA和上皮细胞介导的细胞毒性诱导的凋亡,损害了病毒清除率,并使FMDV持续存在。这些假设的机制为持久性FMDV感染的进一步研究提供了新的信息。

更新日期:2020-06-19
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