The alpha/beta interferon response controls tissue tropism and pathogenicity of poliovirus
The alpha/beta interferon response controls tissue tropism and pathogenicity of poliovirus
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DOI：
10.1128/jvi.79.7.4460-4469.2005
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发表时间：
2005-04-01
影响因子：
5.4
通讯作者：
Koike, S
中科院分区：
文献类型：
--
作者：
Ida-Hosonuma, M;Iwasaki, T;Koike, S
脊髓灰质炎病毒选择性地在脊髓和脑干的神经元中复制，尽管在人类和表达人PVR的转基因小鼠（PVR转基因小鼠）的靶组织和非靶组织中均观察到脊髓灰质炎病毒受体（PVR）表达。我们通过比较PVR转基因小鼠和α/β干扰素受体基因缺陷的PVR转基因小鼠（PVR转基因/Ifnar敲除小鼠）中强毒马奥尼菌株的发病机制，评估了α/β干扰素（IFN）在确定组织嗜性中的作用。PVR转基因/Ifnar基因敲除小鼠对脊髓灰质炎病毒的易感性增加。静脉接种后，除中枢神经系统外，还在肝脏、脾脏和胰腺中检测到脊髓灰质炎病毒抗原阳性的严重病变。这些结果表明，α/β干扰素系统在确定组织嗜性中起着重要作用，通过保护潜在易受感染的非靶组织。我们随后检查了干扰素和干扰素刺激基因（ISGs）在PVR转基因小鼠中的表达。在非靶组织中，ISGs即使在未感染状态下也表达，并且在脊髓灰质炎病毒感染后不久表达水平增加。相反，在靶组织中，在未感染状态下ISG表达较低，并且在脊髓灰质炎病毒感染后未观察到足够的应答。结果表明，不同的IFN应答是组织对脊髓灰质炎病毒不同易感性的重要决定因素之一。我们认为，脊髓灰质炎病毒复制中观察到的PVR转基因/Ifnar基因敲除小鼠的非靶组织，因为IFN反应是无效的，在所有组织。
Poliovirus selectively replicates in neurons in the spinal cord and brainstem, although poliovirus receptor (PVR) expression is observed in both the target and nontarget tissues in humans and transgenic mice expressing human PVR (PVR-transgenic mice). We assessed the role of alpha/beta interferon (IFN) in determining tissue tropism by comparing the pathogenesis of the virulent Mahoney strain in PVR-transgenic mice and PVR-transgenic mice deficient in the alpha/beta IFN receptor gene (PVR-transgenic/Ifnar knockout mice). PVR-transgenic/Ifnar knockout mice showed increased susceptibility to poliovirus. After intravenous inoculation, severe lesions positive for the poliovirus antigen were detected in the liver, spleen, and pancreas in addition to the central nervous system. These results suggest that the alpha/beta IFN system plays an important role in determining tissue tropism by protecting nontarget tissues that are potentially susceptible to infection. We subsequently examined the expression of IFN and IFN-stimulated genes (ISGs) in the PVR-transgenic mice. In the nontarget tissues, ISGs were expressed even in the noninfected state, and the expression level increased soon after poliovirus infection. On the contrary, in the target tissues, ISG expression was low in the noninfected state and sufficient response after poliovirus infection was not observed. The results suggest that the unequal IFN response is one of the important determinants for the differential susceptibility of tissues to poliovirus. We consider that poliovirus replication was observed in the nontarget tissues of PVR-transgenic/Ifnar knockout mice because the IFN response was null in all tissues.