Impaired long-chain fatty acid metabolism in mitochondria causes brain vascular invasion by a non-neurotropic epidemic influenza A virus in the newborn/suckling period: implications for influenza-associated encephalopathy
Impaired long-chain fatty acid metabolism in mitochondria causes brain vascular invasion by a non-neurotropic epidemic influenza A virus in the newborn/suckling period: implications for influenza-associated encephalopathy
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DOI：
10.1007/s11010-005-9046-x
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发表时间：
2007-05
影响因子：
4.3
通讯作者：
D. Yao;M. Kuwajima;Ye Chen;M. Shiota;Y. Okumura;H. Yamada;H. Kido
中科院分区：
文献类型：
--
作者：
D. Yao;M. Kuwajima;Ye Chen;M. Shiota;Y. Okumura;H. Yamada;H. Kido
儿童流感相关脑病和雷氏综合征的神经发病机制尚不清楚。2000-2003年期间在日本西南部开展的一项监测工作显示，几乎所有致命性和致残性流感相关脑病患者都表现出线粒体β氧化紊乱，血清酰基肉碱比值(C16:0+C18:1)/C2升高。本研究显示，在先天性或新生儿/哺乳期线粒体β氧化受损的小鼠鼻内感染后，非嗜神经性流行性甲型H3N2流感病毒侵入脑毛细血管，并伴有进行性脑水肿。与野生型小鼠相比，遗传上缺乏肉毒碱转运体OCTN2导致肉毒碱缺乏和β-氧化受损的小鼠，在大脑中表现出明显更高的病毒基因组数量，病毒抗原仅在脑毛细血管中积累，并且脑血管通透性增加。迷你纤溶酶是一种蛋白水解增强流感病毒在体内增殖并破坏血脑屏障的物质，它与病毒抗原一起在octn2缺陷小鼠的脑毛细血管中积累，但在野生型小鼠中只有少量。这些结果表明，线粒体β-氧化受损改变了非嗜神经型甲型流感病毒在脑毛细血管中的增殖和引起脑水肿的易感性。在流感病毒感染后线粒体β氧化受损的小鼠大脑中的这些病理发现可能对人类流感相关脑病有影响。
The neuropathogenesis of influenza-associated encephalopathy in children and Reye's syndrome remains unclear. A surveillance effort conducted during 2000-2003 in South-West Japan reveals that almost all fatal and handicapped influenza-associated encephalopathy patients exhibit a disorder of mitochondrial β-oxidation with elevated serum acylcarnitine ratios (C16:0+C18:1)/C2. Here we show invasion by a non-neurotropic epidemic influenza A H3N2 virus in cerebral capillaries with progressive brain edema after intranasal infection of mice having impaired mitochondrial β-oxidation congenitally or posteriorly in the newborn/ suckling periods. Mice genetically lacking of carnitine transporter OCTN2, resulting in carnitine deficiency and impaired β-oxidation, exhibited significant higher virus-genome numbers in the brain, accumulation of virus antigen exclusively in the cerebral capillaries and increased brain vascular permeability compared to in wild type mice. Mini-plasmin, which proteolytically potentiates influenza virus multiplicationin vivoand destroys the blood-brain barrier, accumulated with virus antigen in the brain capillaries of OCTN2-deficient mice but only a little in wild-type mice. These results suggest that the impaired mitochondrial β-oxidation changes the susceptibility to a non-neurotropic influenza A virus as to multiplication in the brain capillaries and to cause brain edema. These pathological findings in the brain of mice having impaired mitochondrial β-oxidation after influenza virus infection may have implications for human influenza-associated encephalopathy.