Limited brain metabolism changes differentiate between the progression and clearance of rabies virus.
Limited brain metabolism changes differentiate between the progression and clearance of rabies virus.
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DOI：
10.1371/journal.pone.0087180
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Faber M
中科院分区：
文献类型：
--
作者：
Schutsky K;Portocarrero C;Hooper DC;Dietzschold B;Faber M
研究人员对狂犬病毒（RABV）感染小鼠的中枢神经系统（CNS）代谢谱进行了检测，这些小鼠分别接受单剂量重组RABV活疫苗TriGAS的模拟处理或暴露后处理（PET）。从感染中晚期的模拟治疗小鼠身上采集的中枢神经系统组织显示，与病毒RNA复制水平相关的能量代谢物、神经递质和应激激素发生了许多变化。虽然在TriGAS治疗的小鼠大脑中，大部分代谢变化完全不存在，这很可能是由于病毒传播的强烈减少，但TriGAS治疗导致肉毒碱和几种酰基肉毒碱的表达上调，这表明这些化合物具有神经保护作用。在rabv感染的模拟治疗小鼠中，最显著的变化是脑皮质酮和血清皮质酮水平的急剧增加，后者在出现临床症状或体重减轻之前升高。我们推测皮质酮的升高是RABV策略的一部分，以阻止免疫反应的诱导，否则会干扰其传播。为了支持这一概念，我们表明，在没有疫苗治疗的情况下，通过药物干预抑制皮质酮的生物合成，可显著降低RABV的致病性。我们的研究结果表明，广泛的代谢变化，包括下丘脑-垂体-肾上腺轴的激活，有助于RABV的发病机制，并且在感染早期通过PET或药物阻断预防这些改变有助于保护大脑稳态，从而降低疾病死亡率。
Central nervous system (CNS) metabolic profiles were examined from rabies virus (RABV)-infected mice that were either mock-treated or received post-exposure treatment (PET) with a single dose of the live recombinant RABV vaccine TriGAS. CNS tissue harvested from mock-treated mice at middle and late stage infection revealed numerous changes in energy metabolites, neurotransmitters and stress hormones that correlated with replication levels of viral RNA. Although the large majority of these metabolic changes were completely absent in the brains of TriGAS-treated mice most likely due to the strong reduction in virus spread, TriGAS treatment resulted in the up-regulation of the expression of carnitine and several acylcarnitines, suggesting that these compounds are neuroprotective. The most striking change seen in mock-treated RABV-infected mice was a dramatic increase in brain and serum corticosterone levels, with the later becoming elevated before clinical signs or loss of body weight occurred. We speculate that the rise in corticosterone is part of a strategy of RABV to block the induction of immune responses that would otherwise interfere with its spread. In support of this concept, we show that pharmacological intervention to inhibit corticosterone biosynthesis, in the absence of vaccine treatment, significantly reduces the pathogenicity of RABV. Our results suggest that widespread metabolic changes, including hypothalamic-pituitary-adrenal axis activation, contribute to the pathogenesis of RABV and that preventing these alterations early in infection with PET or pharmacological blockade helps protect brain homeostasis, thereby reducing disease mortality.
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影响因子：
9.8
作者：
Hampson K;Dushoff J;Cleaveland S;Haydon DT;Kaare M;Packer C;Dobson A
通讯作者：
Dobson A
影响因子：
5.4
作者：
Jackson, AC;Rossiter, JP
通讯作者：
Rossiter, JP
DOI：
10.1007/bf01250574
发表时间：
1991-01-01
期刊：
JOURNAL OF NEURAL TRANSMISSION-GENERAL SECTION
影响因子：
--
作者：
JANIRI, L;FALCONE, M;TEMPESTA, E
通讯作者：
TEMPESTA, E
影响因子：
3.2
作者：
Dhingra, Vikas;Li, Xiaqing;Fu, Zhen F.
通讯作者：
Fu, Zhen F.
影响因子：
5.4
作者：
Hooper, DC;Morimoto, K;Dietzschold, B
通讯作者：
Dietzschold, B