Hippocampal protection in mice with an attenuated inflammatory monocyte response to acute CNS picornavirus infection

Howe, Charles L.; LaFrance‐Corey, Reghann G.; Sundsbak, Rhianna S.; Sauer, Brian M.; LaFrance, Stephanie J.; Buenz, Eric J.; Schmalstieg, William F.

doi:10.1038/srep00545

Cited by 43 publications

(70 citation statements)

References 65 publications

(85 reference statements)

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“…Peripheral macrophages were one of the dominant cell-types infiltrating the brain (Cusick et al, 2013; Howe et al, 2012a, b) and these cells were involved in the development of acute seizures following TMEV-DA infection (Cusick et al, 2013). As TMEV antigen was not detected in the CNS following TMEV-H101 infection (Cusick et al, 2014; Libbey et al, 2011b) despite the fact that virus is administered directly into the brain (i.c.…”

Section: Resultsmentioning

confidence: 99%

The role of peripheral interleukin-6 in the development of acute seizures following virus encephalitis

et al. 2017

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Seizure disorders are often associated with infectious etiologies. Infection, via the intracerebral (i.c.) route, of C57BL/6J mice with the Daniels (DA) strain of Theiler’s murine encephalomyelitis virus (TMEV) results in approximately 50% of the mice developing acute behavioral seizures. TMEV-DA is the wild-type strain of the virus that replicates within the parenchyma of the brain. A variant of TMEV-DA, TMEV-H101, does not replicate within the parenchyma of the brain. However, infection with TMEV-H101 via the i.c. route still results in approximately 40% of the mice developing acute behavioral seizures. Infiltrating macrophages producing interleukin-6 (IL-6) have been implicated in the induction of acute seizures following TMEV-DA infection. We examined macrophage infiltration and microglial activation within the brain and cytokine levels in the periphery in mice infected with TMEV-DA or TMEV-H101, and assessed the effects of the addition of recombinant IL-6 to the periphery in wild-type and IL-6 knockout mice infected with TMEV-DA. We found that pathologic levels of IL-6 in the periphery may play a role in the development of seizures when viral replication within the brain is limited. Examination of the role played by the peripheral immune system in the development of seizures/epilepsy in the TMEV-induced seizure model, the first viral infection driven model for epilepsy, could lead to the elucidation of novel therapeutics.

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Section: Resultsmentioning

confidence: 99%

The role of peripheral interleukin-6 in the development of acute seizures following virus encephalitis

et al. 2017

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“…At the indicated times after infection, mice were sacrificed, and white blood cells in submandibular lymph nodes and/ or spleens were isolated as described previously (8). For isolation of white blood cells in brain stems, eyes, or TGs, each tissue from infected mice was cut into small pieces; incubated in RPMI 1640 containing 2% fetal calf serum, 1 mg collagenase D/ml (Wako), and 15 μg DNase I (Roche)/ml for 30 minutes at 37°C; filtered through a 70-μm-poresize filter; suspended in 15 ml 30% Percoll (GE Healthcare) in RPMI 1640; and centrifuged at 7,800 g for 30 minutes at room temperature (55). The myelin debris at the top of the brain stem or TG samples was removed, and the layer containing white blood cells above the red blood cell layer was collected and washed.…”

Section: Histopathology and Immunohistochemistrymentioning

confidence: 99%

Herpes simplex virus-1 evasion of CD8+ T cell accumulation contributes to viral encephalitis

Koyanagi¹,

Imai²,

Shindo³

et al. 2017

Journal of Clinical Investigation

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to β-actin (AC15; Sigma-Aldrich), donkey anti-goat IgG-HRP (sc-2020; Santa Cruz Biotechnology Inc.), and sheep anti-mouse IgG, HRPlinked F(ab′) 2 fragment (NA9310; GE) were used for immunoblotting.Statistics. Differences in β-actin mRNA amounts and antigen presentation were statistically analyzed by 1-way ANOVA followed by Tukey's post-test. Differences in survival of infected mice were statistically analyzed by the log-rank test. Differences in other data were statistically analyzed by the Mann-Whitney U test. A P value of 0.05 or less was considered statistically significant.

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“…Five-to -week-old female p53 Ϫ/Ϫ ICR mice and littermate control p53 ϩ/ϩ ICR mice were infected intracranially with 100 PFU of HSV-1(F) as described above. For isolation of white blood cells from the brains, at 6 days postinfection, the brains from infected mice were cut into small pieces, incubated in RPMI 1640 containing 2% fetal calf serum, 1 mg collagenase D (Wako)/ml, and 15 g DNase I (Roche)/ml for 30 min at 37°C, filtered through a 70-m-pore-size filter, suspended in 15 ml 30% Percoll (GE Healthcare) in RPMI 1640, and centrifuged at 7,800 ϫ g for 30 min at room temperature (22). The myelin debris on the top was removed, and the layer containing white blood cells above the red blood cell layer was collected and washed.…”

Section: Mice and Virus P53-deficient (P53mentioning

confidence: 99%

“…All animal experiments were carried out in accordance with the Guidelines for Proper Conduct of Animal Experiments of the Science Council of Japan (20). The protocol was approved by the Institutional Animal Care and Use Committee, Institute of Medical Science, the University of Tokyo (IACUC protocol approval [19][20][21][22][23][24][25][26].…”

Section: Mice and Virus P53-deficient (P53mentioning

confidence: 99%

p53 Is a Host Cell Regulator during Herpes Simplex Encephalitis

Maruzuru

Koyanagi

Takemura

et al. 2016

J Virol

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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...

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Hippocampal protection in mice with an attenuated inflammatory monocyte response to acute CNS picornavirus infection

Cited by 43 publications

References 65 publications

The role of peripheral interleukin-6 in the development of acute seizures following virus encephalitis

The role of peripheral interleukin-6 in the development of acute seizures following virus encephalitis

Herpes simplex virus-1 evasion of CD8+ T cell accumulation contributes to viral encephalitis

p53 Is a Host Cell Regulator during Herpes Simplex Encephalitis

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