Neutrophil and macrophage influx into the central nervous system are inflammatory components of lethal Rift Valley fever encephalitis in rats
Neutrophil and macrophage influx into the central nervous system are inflammatory components of lethal Rift Valley fever encephalitis in rats
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DOI：
10.1371/journal.ppat.1007833
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发表时间：
2019-06-01
期刊：
影响因子：
6.7
通讯作者：
Hartman, Amy L.
中科院分区：
文献类型：
--
作者：
Albe, Joseph R.;Boyles, Devin A.;Hartman, Amy L.
裂谷热病毒（RVFV）在牲畜中引起严重疾病，同时人畜共患病传播给人类。感染RVFV的一部分人会发展为脑炎，我们对RVFV如何导致大脑病理学的认识仍存在重大空白。我们以前发现，在刘易斯大鼠，皮下接种RVFV导致亚临床疾病，而吸入RVFV的小颗粒气溶胶引起致命的脑炎。本文通过比较RVFV在刘易斯大鼠不同接种途径后的病程变化，进一步了解致死性RVFV脑炎的发病机制。在患有致命脑炎的气溶胶感染大鼠中，中性粒细胞和巨噬细胞是浸润中枢神经系统的主要细胞类型，这伴随着小胶质细胞活化和广泛的细胞因子炎症。尽管如此，防止中性粒细胞浸润到脑中并没有改善疾病。出乎意料的是，在皮下接种的亚临床疾病大鼠中，在脑中发现可检测到的病毒RNA沿着T细胞浸润。裂谷热是一种在非洲和中东部分地区周期性发生的牲畜和人类疾病，它是一种由非洲裂谷热病毒引起的疾病。感染裂谷热病毒的人可能会出现不同的临床结果，包括出血热或脑炎。由于神经系统疾病的动物模型不足，对脑炎的病理生理机制的理解一直是一个挑战。我们使用裂谷热脑炎的大鼠模型来了解与亚临床感染相比致命神经系统疾病的潜在机制。浸润致死性脑炎大鼠大脑的主要免疫细胞类型是中性粒细胞和巨噬细胞。阻止中性粒细胞迁移到大脑中并不能预防疾病。这些结果提供了新的洞察力之间的对比致死和亚临床疾病的免疫活性啮齿动物模型裂谷热脑炎。
Rift Valley fever virus (RVFV) causes severe disease in livestock concurrent with zoonotic transmission to humans. A subset of people infected with RVFV develop encephalitis, and significant gaps remain in our knowledge of how RVFV causes pathology in the brain. We previously found that, in Lewis rats, subcutaneous inoculation with RVFV resulted in subclinical disease while inhalation of RVFV in a small particle aerosol caused fatal encephalitis. Here, we compared the disease course of RVFV in Lewis rats after each different route of inoculation in order to understand more about pathogenic mechanisms of fatal RVFV encephalitis. In aerosol-infected rats with lethal encephalitis, neutrophils and macrophages were the major cell types infiltrating the CNS, and this was concomitant with microglia activation and extensive cytokine inflammation. Despite this, prevention of neutrophil infiltration into the brain did not ameliorate disease. Unexpectedly, in subcutaneously-inoculated rats with subclinical disease, detectable viral RNA was found in the brain along with T-cell infiltration. This study sheds new light on the pathogenic mechanisms of RVFV encephalitis.Author summary Rift Valley fever is a disease of livestock and humans that occurs periodically in Africa and parts of the Middle East. People infected with Rift Valley fever virus can develop different clinical outcomes, including hemorrhagic fever or encephalitis. Understanding of the pathophysiological mechanisms of encephalitis has been a challenge due to inadequate animal models of neurological disease. We used a rat model of Rift Valley fever encephalitis to understand the mechanisms underlying lethal neurological disease compared to subclinical infection. The primary immune cell types that infiltrate the brains of rats with lethal encephalitis were neutrophils and macrophages. Prevention of neutrophil migration into the brains did not prevent disease. These results provide new insight into the contrast between lethal and subclinical disease in an immunocompetent rodent model of Rift Valley fever encephalitis.