Overexpression of tumor necrosis factor alpha by a recombinant rabies virus attenuates replication in neurons and prevents lethal infection in mice
Overexpression of tumor necrosis factor alpha by a recombinant rabies virus attenuates replication in neurons and prevents lethal infection in mice
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DOI：
10.1128/jvi.79.24.15405-15416.2005
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发表时间：
2005-12-01
影响因子：
5.4
通讯作者：
Weihe, E
中科院分区：
文献类型：
--
作者：
Faber, M;Bette, M;Weihe, E
研究了肿瘤坏死因子-α（TNF-α）对狂犬病病毒（RV）感染小鼠中枢神经系统（CNS）的影响，使用重组RV工程化表达可溶性TNF-α [SPBN-TNF-α（+）]或不溶性膜结合TNF-α [SPBN-TNF-α（MEM）]。小鼠神经母细胞瘤NA细胞感染的生长曲线显示，SPBN-TNF-α（+）的扩散和产生明显少于SPBN-TNF-α（MEM）或SPBN-TNF-α（-），后者携带失活的TNF-α基因。可溶性或膜结合TNF-α的表达与细胞死亡增加或α/β干扰素诱导无关。鼻内感染SPBN-TNF-α（+）的小鼠大脑显示出比SPBN-TNF-α（-）感染后的小鼠大脑明显更少的病毒传播，并且没有SPBN-TNF-α（+）感染的小鼠死于RV感染，而80%的SPBN-TNF-α（-）感染的小鼠死亡。在SPBN-TNF-α（+）感染的小鼠脑中，病毒传播减少被增强的CNS炎症所抵消，包括T细胞浸润和小胶质细胞活化。这些数据表明，TNF-α直接通过一种未知的抗病毒机制和间接通过诱导CNS中的炎症过程在脑中发挥其保护活性。
The effect of tumor necrosis factor alpha (TNF-alpha) on rabies virus (RV) infection of the mouse central nervous system (CNS) was studied, using recombinant RV engineered to express either soluble TNF-alpha [SPBN-TNF-alpha(+)] or insoluble membrane-bound TNF-alpha [SPBN-TNF-alpha(MEM)]. Growth curves derived from infections of mouse neuroblastoma NA cells revealed significantly less spread and production of SPBN-TNF-alpha(+) than of SPBN-TNF-alpha(MEM) or SPBN-TNF-alpha(-), which carries an inactivated TNF-alpha gene. The expression of soluble or membrane-bound TNF-alpha was not associated with increased cell death or induction of alpha/beta interferons. Brains of mice infected intranasally with SPBN-TNF-alpha(+) showed significantly less virus spread than did mouse brains after SPBN-TNF-alpha(-) infection, and none of the SPBN-TNF-alpha(+)infected mice succumbed to RV infection, whereas 80% of SPBN-TNF-alpha(-)-infected mice died. Reduced virus spread in SPBN-TNF-alpha(+)-infected mouse brains was paralleled by enhanced CNS inflammation, including T-cell infiltration and microglial activation. These data suggest that TNF-alpha exerts its protective activity in the brain directly through an as yet unknown antiviral mechanism and indirectly through the induction of inflammatory processes in the CNS.