Novel mechanism of arenavirus-induced liver pathology.
Novel mechanism of arenavirus-induced liver pathology.
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DOI：
10.1371/journal.pone.0122839
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Lukashevich IS
中科院分区：
文献类型：
--
作者：
Beier JI;Jokinen JD;Holz GE;Whang PS;Martin AM;Warner NL;Arteel GE;Lukashevich IS
病毒性出血热（vhf）包括一组以发热、出血和休克为主要症状的疾病。肝脏是甚高频发病的重要媒介，血浆中高水平的ALT/AST转氨酶与不良预后相关。事实上，拉沙热（LF）是非洲最流行的甚高频，最初临床描述为肝炎。先前在非人类灵长类动物（NHP）模型中的研究也将LF发病机制与肝脏中强大的增殖反应联系起来。本研究的目的是深入了解肝损伤的机制，并确定增殖在LF发病机制中的潜在作用。C57Bl/6J小鼠分别感染致病性（NHPs）淋巴细胞脉络丛脑膜炎病毒（LCMV，原型沙粒病毒）LCMV- we和非致病性LCMV- arm。正如预期的那样，LCMV-WE而不是ARM引起了肝炎样感染。LCMV-WE还诱导了活跃循环肝细胞数量的显著增加。尽管增殖增加，但LCMV-WE和LCMV-ARM之间的肝脏大小没有显著差异，表明细胞周期不完整。事实上，细胞在G1期出现阻滞，LCMV-WE感染增加了同时染色增殖和凋亡的肝细胞数量。LCMV-WE感染还诱导了一种来自TAM （TYRO3/AXL/MERTK）受体酪氨酸激酶家族的非传统病毒受体AXL-1的表达，这种表达与增殖相关。综上所述，这些结果为肝脏参与VHF发病机制提供了新的思路。具体来说，假设肝细胞增殖的诱导有助于扩大实质细胞的感染。血浆转氨酶水平升高可能是由感染引起的细胞周期中止导致的，至少是部分原因。这些结果可能会导致新的治疗方法的发展，以防止甚高频进展。
Viral hemorrhagic fevers (VHFs) encompass a group of diseases with cardinal symptoms of fever, hemorrhage, and shock. The liver is a critical mediator of VHF disease pathogenesis and high levels of ALT/AST transaminases in plasma correlate with poor prognosis. In fact, Lassa Fever (LF), the most prevalent VHF in Africa, was initially clinically described as hepatitis. Previous studies in non-human primate (NHP) models also correlated LF pathogenesis with a robust proliferative response in the liver. The purpose of the current study was to gain insight into the mechanism of liver injury and to determine the potential role of proliferation in LF pathogenesis. C57Bl/6J mice were infected with either the pathogenic (for NHPs) strain of lymphocytic choriomeningitis virus (LCMV, the prototypic arenavirus), LCMV-WE, or with the non-pathogenic strain, LCMV-ARM. As expected, LCMV-WE, but not ARM, caused a hepatitis-like infection. LCMV-WE also induced a robust increase in the number of actively cycling hepatocytes. Despite this increase in proliferation, there was no significant difference in liver size between LCMV-WE and LCMV-ARM, suggesting that cell cycle was incomplete. Indeed, cells appeared arrested in the G1 phase and LCMV-WE infection increased the number of hepatocytes that were simultaneously stained for proliferation and apoptosis. LCMV-WE infection also induced expression of a non-conventional virus receptor, AXL-1, from the TAM (TYRO3/AXL/MERTK) family of receptor tyrosine kinases and this expression correlated with proliferation. Taken together, these results shed new light on the mechanism of liver involvement in VHF pathogenesis. Specifically, it is hypothesized that the induction of hepatocyte proliferation contributes to expansion of the infection to parenchymal cells. Elevated levels of plasma transaminases are likely explained, at least in part, by abortive cell cycle arrest induced by the infection. These results may lead to the development of new therapies to prevent VHF progression.
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影响因子：
13.5
作者：
Fletcher, Nicola F.;Sutaria, Rupesh;Jo, Juandy;Barnes, Amy;Blahova, Miroslava;Meredith, Luke W.;Cosset, Francois-Loic;Curbishley, Stuart M.;Adams, David H.;Bertoletti, Antonio;McKeating, Jane A.
通讯作者：
McKeating, Jane A.
DOI：
10.1124/jpet.108.136721
发表时间：
2008-06-01
影响因子：
3.5
作者：
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作者：
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通讯作者：
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影响因子：
13.5
作者：
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影响因子：
3.8
作者：
Arteel, Gavin E.;Guo, Luping;States, J. Christopher
通讯作者：
States, J. Christopher