Cytomegalovirus induces interferon-stimulated gene expression and is attenuated by interferon in the developing brain
Cytomegalovirus induces interferon-stimulated gene expression and is attenuated by interferon in the developing brain
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DOI：
10.1128/jvi.01592-06
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发表时间：
2007-01-01
影响因子：
5.4
通讯作者：
Wollmann, Guido
中科院分区：
文献类型：
--
作者：
van den Pol, Anthony N.;Robek, Michael D.;Wollmann, Guido
巨细胞病毒（CMV）被认为是导致发育中的大脑永久性神经功能障碍的最常见的感染性病原体。我们之前的研究表明，巨细胞病毒感染发育中的脑细胞比感染成熟的脑细胞更容易，而且这种偏好与宿主B细胞和t细胞的反应无关。在本研究中，我们检测了小鼠(m)和人类(h)在发育和成熟的大脑和脑细胞中对cmv的先天抗病毒防御。mCMV感染诱导干扰素（IFN）刺激的基因表达在胶质细胞和神经元富集培养中增加10- 100倍。用ifn - α， - β和- γ或合成RNA poly（I:C）处理原代脑培养物，减少了mcw感染细胞的数量，无论是在老细胞中还是在胚胎小鼠脑的新鲜培养物中。当使用杀死几乎所有未受保护的细胞的病毒剂量时，ifn保护的细胞具有自然外观，当使用全细胞膜片钳记录测试时，它们具有典型的静息膜电位和动作电位，在生理上表现正常。mCMV感染增加了新生儿和成人大脑中具有代表性的ifn刺激基因（IFIT3、OAS、LMP2、TGTP和USP18）的表达，程度相似。新生儿大脑中基因表达的强烈上调与这一发育阶段病毒复制的高度相关。与下游基因诱导的情况相反，巨细胞病毒在成人大脑中上调ifn - α / β表达的程度大于在新生儿大脑中。与培养的脑细胞类似，IFN在体内处理发育中的大脑可以抑制mCMV的复制。在培养的原代人脑细胞的平行研究中，IFN和poly（I:C）治疗可减少hCMV感染并防止病毒介导的细胞死亡。这些结果表明，将IFN与目前的治疗相结合可能会减少发育中的大脑中的巨细胞病毒感染。
Cytomegalovirus (CMV) is considered the most common infectious agent causing permanent neurological dysfunction in the developing brain. We have previously shown that CMV infects developing brain cells more easily than it infects mature brain cells and that this preference is independent of the host B- and T-cell responses. In the present study, we examined the innate antiviral defenses against mouse (m) and human (h) CMVs in developing and mature brain and brain cells. mCMV infection induced interferon (IFN)-stimulated gene expression by 10- to 100-fold in both glia- and neuron-enriched cultures. Treatment of primary brain cultures with IFN-alpha, -beta, and -gamma or a synthetic RNA, poly(I:C), reduced the number of mCW-infected cells, both in older cells and in fresh cultures from embryonic mouse brains. When a viral dose that killed almost all unprotected cells was used, IFN-protected cells had a natural appearance, and when they were tested with whole-cell patch clamp recording, they appeared physiologically normal with typical resting membrane potentials and action potentials. mCMV infection increased expression of representative IFN-stimulated genes (IFIT3, OAS, LMP2, TGTP, and USP18) in both neonatal and adult brains to similarly large degrees. The robust upregulation of gene expression in the neonatal brain was associated with a much higher degree of viral replication at this stage of development. In contrast to the case for downstream gene induction, CMV upregulated IFN-alpha/beta expression to a greater degree in the adult brain than in the neonatal brain. Similar to the case with cultured brain cells, IFN treatment of the developing brain in vivo depressed mCMV replication. In parallel work with cultured primary human brain cells, IFN and poly(I:C) treatment reduced hCMV infection and prevented virus-mediated cell death. These results suggest that coupling IFN administration with current treatments may reduce CMV infections in the developing brain.