淋巴细胞胆膜炎病毒的致病性和无病性菌株具有不同的入口和先天免疫激活途径
Dylan M Johnson1,2,3,4, Nittaya Khakhum3, Min Wang5
1Center for Predictive Medicine for Biodefense and Emerging Infectious Diseases, Louisville, KY 94202, USA.
致病性LCMV-WE避免了先天的免疫感应,与减弱的LCMV-ARM不同,它会触发强大的反应. 细胞进入和贩运的差异解释了为什么LCMV-ARM会激活免疫细胞,促进对淋巴细胞冠状腺炎病毒的有效反应.
科学领域:
- 病毒学 病毒学
- 免疫学 免疫学 免疫学
- 细胞生物学 细胞生物学
背景情况:
- 淋巴细胞胆膜炎病毒 (LCMV) 和拉萨病毒 (LASV) 具有遗传相似性,具有不同的致病性 (LCMV-WE) 和减弱 (LCMV-ARM) 菌株.
- 在非人类灵长类动物 (NHPs) 中,LCMV-WE会导致致命性肝炎,而LCMV-ARM则被减弱并对NHPs中的LCMV-WE挑战有保护作用.
研究的目的:
- 研究LCMV-WE和LCMV-ARM菌株不同致病性背后的细胞差异机制.
- 阐明细胞进入途径,先天性免疫感应和细胞内贩运在LCMV病原和免疫反应中的作用.
主要方法:
- 在细胞培养和非人类灵长类动物中对LCMV-WE和LCMV-ARM感染的比较分析.
- 对胆固醇消耗和内体酸性化细胞吸收敏感性的评估.
- 使用双报告器细胞测量NF-κB和干扰素响应因子 (IRF) 激活.
- 调查托尔类受体2 (TLR-2) 信号传递和介素-1受体相关激酶1 (IRAK-1) 表达.
- 聚焦显微镜用于分析细胞内贩运和同局部化与内体标志物 (EEA1,Rab-7).
主要成果:
- LCMV-WE的进入依赖于胆固醇,而LCMV-ARM则依赖于内体酸性化.
- LCMV-ARM诱导了强大的NF-κB和IRF激活,而LCMV-WE则回避了早期的先天感应.
- 对于LCMV-ARM诱导的IL-6产生来说,TLR-2信号非常重要,但对于LCMV-WE来说却不是.
- LCMV-ARM感染导致IRAK-1表达的减少,这表明它在NF-κB激活中的作用.
- 与LCMV-WE.相比,LCMV-ARM在早期内体中与TLR-2具有更大的共同局部化.
结论:
- LCMV-ARM独特的细胞内贩运促进了与先天免疫传感器的相互作用,促进了有效的免疫反应.
- LCMV-WE的致病机制涉及逃避早期先天性免疫识别和TLR-2-依赖性细胞因子诱导.
- 了解这些菌株特异性的差异对于开发针对LCMV和相关病毒的向抗病毒策略至关重要.
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