p53 Is a Host Cell Regulator during Herpes Simplex Encephalitis

Abstract

ABSTRACTp53 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). 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 pathogenesis in vivo and provides insights into its molecular mechanism, which may suggest novel clinical treatment options for herpes simplex encephalitis. Herpes simplex virus 1 (HSV-1) is an etiological agent in various human mucocutaneous diseases, such as herpes labialis, genital herpes, herpetic whitlow, and keratitis. HSV-1 also causes herpes simplex encephalitis (HSE), which is sporadic and which can be lethal or result in severe neurological defects in a significant fraction of survivors, even with antiviral therapy (1).p53 is a multifunctional host protein that plays a central role in cellular responses to a broad range of stress factors through its regulation of various cellular pathways, such as apoptosis, cell cycling, cellular senescence, DNA repair, autophagy, and innate immune control (2, 3). Since viral infection is a type of stress, it appears that viral infection activates p53 responses that trigger apoptosis of infected cells, thereby suppressing viral replication (4). Thus, when a person is infected with a DNA virus, viral genome replication induces host DNA damage responses (DDRs), which activate apoptotic p53 responses (4). In RNA virus infections, double-stranded RNAs are produced, and these doublestranded RNAs trigger antiviral responses mediated by type I interferon (IFN-I) signaling, in which p53 appears to function as both an upstream and a downstream regulator (5, 6). In agreement with these observation...

p53 and the Viral Connection: Back into the Future ‡

“…On one hand, p53 supports HSV-1 replication by inducing the expression of the viral protein ICP27 that is essential for the HSV-1 replication at early stages of the infection [ 69 ]. This positive p53 regulation was also corroborated in in vivo experiments, where higher HSV-1 replication and mortality rates were noticed in p53WT mice compared with their p53KO counterparts [ 70 ]. On the other hand, p53 mediates the degradation of the viral protein ICP0, which is also essential for both viral replication and a host immune response repression, and by that attenuates HSV-1 replication [ 69 ].…”

Ocular squamous cell carcinoma in Holstein cows from the South of Brazil

“…In experimental studies, viral particles of bovine herpesvirus type 5 were detected in the cytoplasm of bovine OSCC after exposure to UV rays [ 23 ]. It was also discovered that p53 is an important host cell regulator for human herpesvirus replication and pathogenesis [ 51 ]. We consider the lack of herpesvirus and papillomavirus detection in the current study demonstrates that any generalized implication of these viruses playing a role in OSCC carcinogenesis continues to be problematic.…”

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