p53 is a Host Cell Regulator during Herpes Simplex Encephalitis.
p53 is a Host Cell Regulator during Herpes Simplex Encephalitis.
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p53 是单纯疱疹脑炎期间的宿主细胞调节因子。
DOI：
10.1128/jvi.00846-16
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发表时间：
2016
期刊：
影响因子：
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通讯作者：
Kawaguchi Y.
中科院分区：
文献类型：
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作者：
Maruzuru Y;Koyanagi N;Takemura N;Uematsu S;Matsubara D;Suzuki Y;Arii J;Kato A;Kawaguchi Y.
p53是细胞对多种应激因素反应中的关键宿主细胞因子。我们最近报道，p53是需要有效的单纯疱疹病毒1型（HSV-1）在细胞培养中复制。然而，p53在HSV-1复制和体内致病中的明确作用仍然难以捉摸。在这项研究中，我们研究了p53基因对HSV-1感染的影响。颅内接种后，p53基因敲除减少了小鼠脑中的病毒复制，并导致单纯疱疹病毒性脑炎的死亡率显著降低。这些结果表明p53是中枢神经系统（CNS）中HSV-1复制和发病机制的重要宿主细胞调节因子。重要HSV-1引起散发性脑炎病例，即使进行抗病毒治疗，也可导致严重的神经功能缺损甚至死亡。许多参与CNS HSV-1感染调节的宿主细胞因子已使用遗传修饰小鼠进行了研究。然而，这些因子中的大多数是免疫调节剂，并通过免疫途径起作用，以限制CNS HSV-1感染。因此，他们提供的信息有限的内在宿主细胞调节，可能参与促进中枢神经系统HSV-1感染。在这里，我们证明了宿主细胞蛋白，p53，这通常被认为是一种宿主细胞限制因子的各种病毒感染，需要有效的HSV-1复制和发病机制在中枢神经系统的小鼠。这是首次报道p53在体内正调控病毒复制和致病，并揭示了其分子机制，为单纯疱疹病毒性脑炎的临床治疗提供了新的选择。
p53 is a critical host cell factor in the cellular response to a broad range of stress factors. We recently reported that p53 is required for efficient herpes simplex virus 1 (HSV-1) replication in cell culture. However, a defined role for p53 in HSV-1 replication and pathogenesisin vivoremains elusive. In this study, we examined the effects of p53 on HSV-1 infectionin vivousing p53-deficient mice. Following intracranial inoculation, p53 knockout reduced viral replication in the brains of mice and led to significantly reduced rates of mortality due to herpes simplex encephalitis. These results suggest that p53 is an important host cell regulator of HSV-1 replication and pathogenesis in the central nervous system (CNS).IMPORTANCEHSV-1 causes sporadic cases of encephalitis, which, even with antiviral therapy, can result in severe neurological defects and even death. Many host cell factors involved in the regulation of CNS HSV-1 infection have been investigated using genetically modified mice. However, most of these factors are immunological regulators and act via immunological pathways in order to restrict CNS HSV-1 infection. They therefore provide limited information on intrinsic host cell regulators that may be involved in the facilitation of CNS HSV-1 infection. Here we demonstrate that a host cell protein, p53, which has generally been considered a host cell restriction factor for various viral infections, is required for efficient HSV-1 replication and pathogenesis in the CNS of mice. This is the first report showing that p53 positively regulates viral replication and pathogenesisin vivoand provides insights into its molecular mechanism, which may suggest novel clinical treatment options for herpes simplex encephalitis.