The lack of RNA‐dependent protein kinase enhances susceptibility of mice to genital herpes simplex virus type 2 infection

Carr, Daniel J.J.; Wuest, Todd; Tomanek, Lisa; Silverman, Robert H.; Williams, Bryan R.G.

doi:10.1111/j.1365-2567.2006.02403.x

Cited by 7 publications

(4 citation statements)

References 36 publications

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“…Variation was present even between mice from the same litters that that were given HSV-2 on the same day. Other published studies also have reported intra-experiment variability in pathology and time to death of HSV-2 infection [36, 37]. Thus, variability in HSV-2 infection could account for some of the variation in HIV infection observed in our study.…”

Section: Discussionsupporting

confidence: 69%

HSV Type 2 Infection Increases HIV DNA Detection in Vaginal Tissue of Mice Expressing Human CD4 and CCR5

Zariffard

Saifuddin²,

Finnegan³

et al. 2009

AIDS Research and Human Retroviruses

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The goal of this study was to develop an in vivo murine model that can be used to study the influence of HSV-2 on HIV infection. Mice expressing transgenes for human CD4, CCR5 and Cyclin T1 were infected intra-vaginally with HSV-2 and 3-7 days later infected with HIV. HIV DNA was detected by real time PCR. The frequency of detection of HIV DNA was significantly higher (65%) in vaginal tissue of HSV-2-infected mice compared to mock-infected mice (35%) when HIV was given 3 days after HSV-2. HSV-2 infected mice also had significantly higher levels of HIV DNA in vaginal tissue. HIV DNA was not detected in vaginal tissue of mice lacking human CD4. Longer periods (5 or 7 days) between infection with HSV-2 and HIV did not increase the frequency of detection or the amount of HIV DNA detected. HIV DNA was also detected in lymph nodes from some of the mice that were infected intra-vaginally with HSV-2 and HIV. Flow cytometric and mRNA analysis of human CD4 in vaginal tissue suggested that HSV-2 infection increased the number of T cells expressing human CD4 in vaginal tissue. This study provides evidence that HIV infection of cells occurs in the vagina of mice expressing human CD4, CCR5 and Cyclin T1 and that HSV-2 infection increases HIV infection. These findings demonstrate that this model can be used to study the mechanisms responsible for increased susceptibility to HIV in HSV-2-infected persons and for testing preventative treatments.

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Section: Discussionsupporting

confidence: 69%

HSV Type 2 Infection Increases HIV DNA Detection in Vaginal Tissue of Mice Expressing Human CD4 and CCR5

Zariffard

Saifuddin²,

Finnegan³

et al. 2009

AIDS Research and Human Retroviruses

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“…Next, we asked whether the alterations in the behavioral components of sickness of PKR−/− mice would be correlated with exaggerated bacterial load. It has been well reported that loss of PKR can often enhance viral replication [ 41 , 44 , 101 , 102 ]. Another study has shown that PKR is involved in resistance to Toxoplasma gondii [ 45 ].…”

Section: Discussionmentioning

confidence: 99%

PKR deficiency alters E. coli-induced sickness behaviors but does not exacerbate neuroimmune responses or bacterial load

Poon

You

et al. 2015

J Neuroinflammation

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BackgroundSystemic inflammation induces neuroimmune activation, ultimately leading to sickness (e.g., fever, anorexia, motor impairments, exploratory deficits, and social withdrawal). In this study, we evaluated the role of protein kinase R (PKR), a serine-threonine kinase that can control systemic inflammation, on neuroimmune responses and sickness.MethodsWild-type (WT) PKR+/+ mice and PKR−/− mice were subcutaneously injected with live Escherichia coli (E. coli) or vehicle. Food consumption, rotarod test performance, burrowing, open field activity, object investigation, and social interaction were monitored. Plasma TNF-α and corticosterone were measured by ELISA. The percentage of neutrophils in blood was deduced from blood smears. Inflammatory gene expression (IL-1β, TNF-α, IL-6, cyclooxygenase (COX)-2, iNOS) in the liver and the brain (hypothalamus and hippocampus) were quantified by real-time PCR. Blood and lavage fluid (injection site) were collected for microbiological plate count and for real-time PCR of bacterial 16S ribosomal DNA (rDNA). Corticotrophin-releasing hormone (CRH) expression in the hypothalamus was also determined by real-time PCR.ResultsDeficiency of PKR diminished peripheral inflammatory responses following E. coli challenge. However, while the core components of sickness (anorexia and motor impairments) were similar between both strains of mice, the behavioral components of sickness (reduced burrowing, exploratory activity deficits, and social withdrawal) were only observable in PKR−/− mice but not in WT mice. Such alteration of behavioral components was unlikely to be caused by exaggerated neuroimmune activation, by an impaired host defense to the infection, or due to a dysregulated corticosterone response, because both strains of mice displayed similar neuroimmune responses, bacterial titers, and plasma corticosterone profiles throughout the course of infection. Nevertheless, the induction of hypothalamic corticotrophin-releasing hormone (CRH) by E. coli was delayed in PKR−/− mice relative to WT mice, suggesting that PKR deficiency may postpone the CRH response during systemic inflammation.ConclusionsTaken together, our findings show that (1) loss of PKR could alter E. coli-induced sickness behaviors and (2) this was unlikely to be due to exacerbated neuroimmune activation, (3) elevated bacterial load, or (4) dysregulation in the corticosterone response. Further studies can address the role of PKR in the CRH response together with its consequence on sickness.

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“…Studies have shown that mice deficient in RNase L, PKR, or both have a range of pathogenic phenotypes in response to numerous viruses. The viruses tested in these mice include encephalomyocarditis virus [ 31 , 32 ] vesicular stomatitis virus [ 33 , 34 , 35 ], herpes simplex virus types 1 and 2 [ 36 , 37 , 38 ], coxsackievirus B4 [ 39 ], West Nile virus [ 40 ], murine coronavirus [ 41 ], and vaccinia virus [ 42 ]. Depending on the study, pathogenic outcomes for many of these viruses typically include increased mortality, higher viremia and/or viral burden in various tissues, and accelerated onset of clinical disease.…”

Section: Ifn Responses and Isgs In Viral Pathogenesismentioning

confidence: 99%

Interferon-stimulated genes: roles in viral pathogenesis

Schoggins

2014

Current Opinion in Virology

254

237

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Interferon-stimulated genes (ISGs) are critical for controlling virus infections. As new antiviral ISGs continue to be identified and characterized, their roles in viral pathogenesis are also being explored in more detail. Our current understanding of how ISGs impact viral pathogenesis comes largely from studies in knockout mice, with isolated examples from human clinical data. This review outlines recent developments on the contributions of various ISGs to viral disease outcomes in vivo.

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The lack of RNA‐dependent protein kinase enhances susceptibility of mice to genital herpes simplex virus type 2 infection

Cited by 7 publications

References 36 publications

HSV Type 2 Infection Increases HIV DNA Detection in Vaginal Tissue of Mice Expressing Human CD4 and CCR5

HSV Type 2 Infection Increases HIV DNA Detection in Vaginal Tissue of Mice Expressing Human CD4 and CCR5

PKR deficiency alters E. coli-induced sickness behaviors but does not exacerbate neuroimmune responses or bacterial load

Interferon-stimulated genes: roles in viral pathogenesis

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