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Abstract：
Lymphocytic choriomeningitis virus (LCMV) and Lassa virus (LASV) share many genetic and biological features including subtle differences between pathogenic and apathogenic strains. Despite remarkable genetic similarity, the viscerotropic WE strain of LCMV causes a fatal LASV fever-like hepatitis in non-human primates (NHPs) while the mouse-adapted Armstrong (ARM) strain of LCMV is deeply attenuated in NHPs and can vaccinate against LCMV-WE challenge. Here, we demonstrate that internalization of WE is more sensitive to the depletion of membrane cholesterol than ARM infection while ARM infection is more reliant on endosomal acidification. LCMV-ARM induces robust NF-κB and interferon response factor (IRF) activation while LCMV-WE seems to avoid early innate sensing and failed to induce strong NF-κB and IRF responses in dual-reporter monocyte and epithelial cells. Toll-like receptor 2 (TLR-2) signaling appears to play a critical role in NF-κB activation and the silencing of TLR-2 shuts down IL-6 production in ARM but not in WE-infected cells. Pathogenic LCMV-WE infection is poorly recognized in early endosomes and failed to induce TLR-2/Mal-dependent pro-inflammatory cytokines. Following infection, Interleukin-1 receptor-associated kinase 1 (IRAK-1) expression is diminished in LCMV-ARM- but not LCMV-WE-infected cells, which indicates it is likely involved in the LCMV-ARM NF-κB activation. By confocal microscopy, ARM and WE strains have similar intracellular trafficking although LCMV-ARM infection appears to coincide with greater co-localization of early endosome marker EEA1 with TLR-2. Both strains co-localize with Rab-7, a late endosome marker, but the interaction with LCMV-WE seems to be more prolonged. These findings suggest that LCMV-ARM\'s intracellular trafficking pathway may facilitate interaction with innate immune sensors, which promotes the induction of effective innate and adaptive immune responses.
摘要：
淋巴细胞脉络膜脑膜炎病毒（LCMV）和拉沙病毒（LASV）具有许多遗传和生物学特征，包括致病性和无致病性菌株之间的细微差别。尽管有显著的遗传相似性,LCMV的内脏性WE株在非人灵长类动物(NHP)中导致致命的LASV发热样肝炎,而小鼠适应的Armstrong(ARM)LCMV株在NHP中严重减毒,可以接种LCMV-WE攻击疫苗.这里,我们证明WE的内化对膜胆固醇的消耗比ARM感染更敏感，而ARM感染更依赖于内体酸化。LCMV-ARM诱导强大的NF-κB和干扰素反应因子（IRF）激活，而LCMV-WE似乎避免了早期的先天感知，并且未能在双报告单核细胞和上皮细胞中诱导强烈的NF-κB和IRF反应。Toll样受体2（TLR-2）信号传导似乎在NF-κB激活中起关键作用，而TLR-2的沉默会关闭ARM中而不是WE感染的细胞中的IL-6产生。致病性LCMV-WE感染在早期内体中很少被识别，并且未能诱导TLR-2/Mal依赖性促炎细胞因子。感染后,白细胞介素-1受体相关激酶1（IRAK-1）的表达在LCMV-ARM-而不是LCMV-WE感染的细胞中减少，这表明它可能参与了LCMV-ARMNF-κB的激活。通过共聚焦显微镜，ARM和WE菌株具有相似的细胞内运输，尽管LCMV-ARM感染似乎与早期内体标记EEA1与TLR-2的更大共定位相吻合。两种菌株都与晚期内体标记Rab-7共定位，但与LCMV-WE的互动似乎更长时间。这些研究结果表明，LCMV-ARM的细胞内运输途径可能促进与先天免疫传感器的相互作用，促进有效的先天和适应性免疫反应的诱导。
