title: p53 Is a Host Cell Regulator during Herpes Simplex Encephalitis.
abstract: 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 pathogenesis in vivo remains elusive. In this study, we examined the effects of p53 on HSV-1 infection in vivo using 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).
  
  
  
  HSV-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 pathogenesis in vivo and provides insights into its molecular mechanism, which may suggest novel clinical treatment options for herpes simplex encephalitis.
authors.affiliation: Division of Molecular Virology, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.|Division of Viral Infection, Department of Infectious Disease Control, International Research Center for Infectious Diseases, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.|Japan Society for the Promotion of Science, Tokyo, Japan.
authors.forename: Yuhei
authors.initials: Y
authors.lastname: Maruzuru
authors.affiliation: Division of Molecular Virology, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.|Division of Viral Infection, Department of Infectious Disease Control, International Research Center for Infectious Diseases, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
authors.forename: Naoto
authors.initials: N
authors.lastname: Koyanagi
authors.affiliation: International Research and Development Centre for Mucosal Vaccine, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.|Department of Mucosal Immunology, School of Medicine, Chiba University, Chiba, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Takemura
authors.affiliation: International Research and Development Centre for Mucosal Vaccine, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.|Department of Mucosal Immunology, School of Medicine, Chiba University, Chiba, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Uematsu
authors.affiliation: Molecular Pathology Laboratory, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.|Department of Integrative Pathology, Jichi Medical University, Tochigi, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Matsubara
authors.affiliation: Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Kashiwa, Japan.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Suzuki
authors.affiliation: Division of Molecular Virology, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.|Division of Viral Infection, Department of Infectious Disease Control, International Research Center for Infectious Diseases, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Arii
authors.affiliation: Division of Molecular Virology, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.|Division of Viral Infection, Department of Infectious Disease Control, International Research Center for Infectious Diseases, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
authors.forename: Akihisa
authors.initials: A
authors.lastname: Kato
authors.affiliation: Division of Molecular Virology, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan ykawagu@ims.u-tokyo.ac.jp.|Division of Viral Infection, Department of Infectious Disease Control, International Research Center for Infectious Diseases, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Kawaguchi
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology* / Q000821:virology; D020803:Encephalitis, Herpes Simplex / Q000378:metabolism* / Q000401:mortality* / Q000473:pathology / Q000821:virology; D005260:Female; D051379:Mice; D008813:Mice, Inbred ICR; D018345:Mice, Knockout; D018139:Simplexvirus / Q000472:pathogenicity*; D015996:Survival Rate; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*; D014779:Virus Replication
chemical_list: D016159:Tumor Suppressor Protein p53