Comparison of TLR4 Genotype and TLR4 Pathway-Related Cytokines in Different Strains of Mice in Response to Pertussis Toxin Challenge.

IF 2.8 3区生物学 Q2 GENETICS & HEREDITY Genes Pub Date : 2024-11-05 DOI:10.3390/genes15111435

Jie Wei, Lichan Wang, Chen Wei, Jiaona Guang, Hong Wang, Jiaqi Zhou, Huan Li, Xiao Ma, Bingfei Yue

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Abstract

Background: The genetic background of Toll-like receptor 4 (TLR4) proved to be important in the induction of immune protection against Bordetella pertussis infection in humans. Currently, the evaluation of the acellular pertussis (aP) vaccine depends largely on using different mouse strains, while the TLR4 genotype of different mouse strains in response to pertussis toxin (PT) is not carefully determined. The current study was designed to determine the differences in TLR4 genotype and TLR4 pathway-related cytokines in response to PT stimulation among mouse strains of ICR, NIH, and BALB/c.

Method: We first determined the single-nucleotide polymorphisms (SNPs) in the TLR4 gene by using first-generation sequencing. Then, the cellular response, including the TLR4 mRNA expression and TLR4 signaling-related cytokines, of immune cells from different mouse strains after PT stimulation was determined.

Result: Three missense mutation sites (rs13489092, rs13489093, rs13489097) of the TLR4 gene were found. ICR mice were homozygous without mutation, NIH mice were partially heterozygous, and BALB/c mice were homozygous with a missense mutation. The expression of TLR4 was repressed while the downstream cytokines were upregulated after PT stimulation differently among mouse strains. The IFN-β cytokine of the TRIF pathway was significantly increased in ICR mice (p < 0.05). The IL-6 cytokine of the MyD88-dependent pathway was significantly increased in BALB/c mice (p < 0.05). The identified SNPs of the TLR4 gene in different mouse strains might account for the differences in cytokines levels determined after PT stimulation.

Conclusions: Our studies might provide useful referees to reduce the mouse-derived difference in the determination of vaccine titer and increase the comparability of the vaccine from different origins, as different mouse strains were used for vaccine development in different countries.

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比较不同品系小鼠的 TLR4 基因型和 TLR4 通路相关细胞因子对百日咳毒素挑战的反应

背景：事实证明，Toll样受体4（TLR4）的遗传背景在诱导人体对百日咳博德特氏菌感染的免疫保护中起着重要作用。目前，无细胞百日咳（aP）疫苗的评估主要依赖于使用不同的小鼠毒株，而不同小鼠毒株对百日咳毒素（PT）反应的 TLR4 基因型并没有得到仔细确定。本研究旨在确定 ICR、NIH 和 BALB/c 三种小鼠品系的 TLR4 基因型和 TLR4 通路相关细胞因子对 PT 刺激反应的差异：方法：我们首先利用第一代测序技术测定了 TLR4 基因的单核苷酸多态性（SNPs）。然后，测定了不同品系小鼠的免疫细胞在受到 PT 刺激后的细胞反应，包括 TLR4 mRNA 表达和 TLR4 信号相关细胞因子：结果：发现了TLR4基因的三个错义突变位点（rs13489092、rs13489093和rs13489097）。ICR小鼠为无突变的同源突变，NIH小鼠为部分杂合，BALB/c小鼠为有错义突变的同源突变。不同品系的小鼠在受到 PT 刺激后，TLR4 的表达受到抑制，而下游细胞因子则上调。TRIF 通路的 IFN-β 细胞因子在 ICR 小鼠中显著增加（p < 0.05）。BALB/c小鼠中MyD88依赖途径的IL-6细胞因子明显增加（p < 0.05）。在不同品系小鼠中发现的 TLR4 基因 SNPs 可能是 PT 刺激后测定的细胞因子水平存在差异的原因：我们的研究可能为减少疫苗滴度测定中的小鼠来源差异和提高不同来源疫苗的可比性提供了有用的参考，因为不同国家的疫苗开发使用了不同的小鼠品系。

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来源期刊

Genes GENETICS & HEREDITY-

CiteScore

5.20

自引率

5.70%

发文量

1975

审稿时长

22.94 days

期刊介绍： Genes (ISSN 2073-4425) is an international, peer-reviewed open access journal which provides an advanced forum for studies related to genes, genetics and genomics. It publishes reviews, research articles, communications and technical notes. There is no restriction on the length of the papers and we encourage scientists to publish their results in as much detail as possible.