Viral Special Pathogens Branch, Division of High Consequence Pathogens and Pathology, Centers for Disease Control and Prevention, Atlanta, Georgia, United States of America; University of California, Davis, School of Veterinary Medicine, Davis, California, United States of America.
Viral Special Pathogens Branch, Division of High Consequence Pathogens and Pathology, Centers for Disease Control and Prevention, Atlanta, Georgia, United States of America; Emory University School of Medicine, Department of Pediatrics, Atlanta, Georgia, United States of America.
PLoS Negl Trop Dis. 2014 Jun 12;8(6):e2874. doi: 10.1371/journal.pntd.0002874. eCollection 2014 Jun.
Rift Valley fever virus (RVFV) causes outbreaks of severe disease in livestock and humans throughout Africa and the Arabian Peninsula. In people, RVFV generally causes a self-limiting febrile illness but in a subset of individuals, it progresses to more serious disease. One manifestation is a delayed-onset encephalitis that can be fatal or leave the afflicted with long-term neurologic sequelae. In order to design targeted interventions, the basic pathogenesis of RVFV encephalitis must be better understood.
METHODOLOGY/PRINCIPAL FINDINGS: To characterize the host immune responses and viral kinetics associated with fatal and nonfatal infections, mice were infected with an attenuated RVFV lacking NSs (ΔNSs) that causes lethal disease only when administered intranasally (IN). Following IN infection, C57BL/6 mice developed severe neurologic disease and succumbed 7-9 days post-infection. In contrast, inoculation of ΔNSs virus subcutaneously in the footpad (FP) resulted in a subclinical infection characterized by a robust immune response with rapid antibody production and strong T cell responses. IN-inoculated mice had delayed antibody responses and failed to clear virus from the periphery. Severe neurological signs and obtundation characterized end stage-disease in IN-inoculated mice, and within the CNS, the development of peak virus RNA loads coincided with strong proinflammatory responses and infiltration of activated T cells. Interestingly, depletion of T cells did not significantly alter survival, suggesting that neurologic disease is not a by-product of an aberrant immune response.
CONCLUSIONS/SIGNIFICANCE: Comparison of fatal (IN-inoculated) and nonfatal (FP-inoculated) ΔNSs RVFV infections in the mouse model highlighted the role of the host immune response in controlling viral replication and therefore determining clinical outcome. There was no evidence to suggest that neurologic disease is immune-mediated in RVFV infection. These results provide important insights for the future design of vaccines and therapeutic options.
裂谷热病毒（RVFV）会在整个非洲和阿拉伯半岛引发家畜和人类的严重疾病。在人类中，RVFV 通常引起自限性发热疾病，但在一部分个体中，它会发展为更严重的疾病。一种表现是迟发性脑炎，可导致死亡或使患者留下长期神经后遗症。为了设计有针对性的干预措施，必须更好地了解 RVFV 脑炎的基本发病机制。
方法/主要发现：为了描述与致死性和非致死性感染相关的宿主免疫反应和病毒动力学，我们使用一种缺乏 NSs 的 RVFV 减毒株（ΔNSs）感染小鼠，该减毒株仅在经鼻腔（IN）接种时引起致死性疾病。IN 感染后，C57BL/6 小鼠出现严重的神经疾病，并在感染后 7-9 天死亡。相比之下，足底（FP）接种 ΔNSs 病毒会导致亚临床感染，表现为快速产生抗体和强烈的 T 细胞反应的强大免疫反应。IN 接种的小鼠抗体反应延迟，无法从外周清除病毒。IN 接种小鼠的严重神经症状和意识障碍特征为疾病晚期，在中枢神经系统中，病毒 RNA 载量峰值的发展与强烈的促炎反应和活化 T 细胞浸润相一致。有趣的是，耗尽 T 细胞并没有显著改变存活率，这表明神经疾病不是异常免疫反应的副产物。
结论/意义：在小鼠模型中比较致死性（IN 接种）和非致死性（FP 接种）ΔNSs RVFV 感染，突出了宿主免疫反应在控制病毒复制和因此决定临床结果方面的作用。没有证据表明 RVFV 感染中的神经疾病是免疫介导的。这些结果为未来疫苗和治疗选择的设计提供了重要的见解。
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