Host species adaptation of TLR5 signalling and flagellin recognition.
Host species adaptation of TLR5 signalling and flagellin recognition.
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DOI：
10.1038/s41598-017-17935-5
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发表时间：
2017-12-15
影响因子：
4.6
通讯作者：
Glass EJ
中科院分区：
文献类型：
--
作者：
Tahoun A;Jensen K;Corripio-Miyar Y;McAteer S;Smith DGE;McNeilly TN;Gally DL;Glass EJ
Toll样受体5（TLR5）识别鞭毛蛋白引发炎症信号传导。TLR5的显著序列变异存在于动物物种之间，但其对活性的影响尚不清楚。基于我们之前的研究，牛TLR5（bTLR5）是功能性的，我们比较了人类和牛TLR5的活性和信号在同源细胞系。当在牛细胞中表达时，bTLR 5诱导更高水平的CXCL 8，并且在人细胞中发现人TLR 5（hTLR 5）的相反结果，表明该应答中的宿主细胞特异性。Toll/白细胞介素-1受体（TIR）序列的分析表明，这些差异反应涉及同源MyD88识别。siRNA敲除和抑制剂实验表明，在信号传导中存在一些宿主差异。尽管PI3K活化是bTLR 5信号传导所需的，但在推定的PI3K基序内将bTLR 5 F798突变为hTLR 5 Y798导致应答显著降低。与大多数其他物种相比，所有反刍动物都有F798，这表明TLR5信号转导在反刍动物中进化不同。牛和人类TLR5之间的进化差异也是显而易见的，在不同的细菌鞭毛蛋白的反应。我们的研究结果强调了物种特异性研究的重要性，以及差异如何改变基于TLR的疫苗佐剂的功效。
Toll-like receptor 5 (TLR5) recognition of flagellin instigates inflammatory signalling. Significant sequence variation in TLR5 exists between animal species but its impact on activity is less well understood. Building on our previous research that bovine TLR5 (bTLR5) is functional, we compared human and bovine TLR5 activity and signalling in cognate cell lines. bTLR5 induced higher levels of CXCL8 when expressed in bovine cells and reciprocal results were found for human TLR5 (hTLR5) in human cells, indicative of host cell specificity in this response. Analysis of Toll/interleukin-1 receptor (TIR) sequences indicated that these differential responses involve cognate MyD88 recognition. siRNA knockdowns and inhibitor experiments demonstrated that there are some host differences in signalling. Although, PI3K activation is required for bTLR5 signalling, mutating bTLR5 F798 to hTLR5 Y798 within a putative PI3K motif resulted in a significantly reduced response. All ruminants have F798 in contrast to most other species, suggesting that TLR5 signalling has evolved differently in ruminants. Evolutionary divergence between bovine and human TLR5 was also apparent in relation to responses measured to diverse bacterial flagellins. Our results underscore the importance of species specific studies and how differences may alter efficacy of TLR-based vaccine adjuvants.
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