The Type I Interferon Response and Age-Dependent Susceptibility to Herpes Simplex Virus Infection

Giraldo, Daniel; Wilcox, Douglas R.; Longnecker, Richard

doi:10.1089/dna.2017.3668

Cited by 9 publications

(6 citation statements)

References 74 publications

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“…These inconsistent results between studies could be explained by the use of different in vitro models, and could be verified in enteroid models 21 . Interestingly, there is an age‐dependent increase in the ability of monogastrics and ruminants to produce type 1 IFN in response to viral infection, and this difference may also help to explain the increased susceptibility of young children and neonatal cattle to Cryptosporidium infection 101‐103 …”

Section: Defensive Function Of the Intestinal Epithelium Against Crypmentioning

confidence: 99%

Stem cell‐derived enteroid cultures as a tool for dissecting host‐parasite interactions in the small intestinal epithelium

Hares

Tiffney

Johnston

et al. 2020

Parasite Immunology

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Toxoplasma gondii and Cryptosporidium spp. can cause devastating pathological effects in humans and livestock, and in particular to young or immunocompromised individuals. The current treatment plans for these enteric parasites are limited due to long drug courses, severe side effects or simply a lack of efficacy. The study of the early interactions between the parasites and the site of infection in the small intestinal epithelium has been thwarted by the lack of accessible, physiologically relevant and species‐specific models. Increasingly, 3D stem cell‐derived enteroid models are being refined and developed into sophisticated models of infectious disease. In this review, we shall illustrate the use of enteroids to spearhead research into enteric parasitic infections, bridging the gap between cell line cultures and in vivo experiments.

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Section: Defensive Function Of the Intestinal Epithelium Against Crypmentioning

confidence: 99%

Stem cell‐derived enteroid cultures as a tool for dissecting host‐parasite interactions in the small intestinal epithelium

Hares

Tiffney

Johnston

et al. 2020

Parasite Immunology

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“…Mice display an age-dependent acceleration of mortality due to influenza virus (IAV) infection, and are useful for modeling human aging and the outcomes of IAV infection [ 13 ]. It has been suggested that the maturation of the innate immune system and the expression of type I interferon genes may contribute to age-related viral susceptibility [ 14 ]; however, the reason for the differential gene expression patterns between young and adult patients is still unclear.…”

Section: Introductionmentioning

confidence: 99%

Genome-wide DNA methylation reveals potential epigenetic mechanism of age-dependent viral susceptibility in grass carp

Wang

et al. 2022

Immun Ageing

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Background Grass carp are an important farmed fish in China that are infected by many pathogens, especially grass carp reovirus (GCRV). Notably, grass carp showed age-dependent susceptibility to GCRV; that is, grass carp not older than one year were sensitive to GCRV, while those over three years old were resistant to this virus. However, the underlying mechanism remains unclear. Herein, whole genome-wide DNA methylation and gene expression variations between susceptible five-month-old (FMO) and resistant three-year-old (TYO) grass carp were investigated aiming to uncover potential epigenetic mechanisms. Results Colorimetric quantification revealed that the global methylation level in TYO fish was higher than that in FMO fish. Whole-genome bisulfite sequencing (WGBS) of the two groups revealed 6214 differentially methylated regions (DMRs) and 4052 differentially methylated genes (DMGs), with most DMRs and DMGs showing hypermethylation patterns in TYO fish. Correlation analysis revealed that DNA hypomethylation in promoter regions and DNA hypermethylation in gene body regions were associated with gene expression. Enrichment analysis revealed that promoter hypo-DMGs in TYO fish were significantly enriched in typical immune response pathways, whereas gene body hyper-DMGs in TYO fish were significantly enriched in terms related to RNA transcription, biosynthesis, and energy production. RNA-seq analysis of the corresponding samples indicated that most of the genes in the above terms were upregulated in TYO fish. Moreover, gene function analysis revealed that the two genes involved in energy metabolism displayed antiviral effects. Conclusions Collectively, these results revealed genome-wide variations in DNA methylation between grass carp of different ages. DNA methylation and gene expression variations in genes involved in immune response, biosynthesis, and energy production may contribute to age-dependent susceptibility to GCRV in grass carp. Our results provide important information for disease-resistant breeding programs for grass carp and may also benefit research on age-dependent diseases in humans.

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“…This is in stark contrast to adult HSV-1 infections, which are largely asymptomatic or result in benign mucocutaneous disease. Several studies have aimed at studying age-dependent differences in the immune response to HSV-1 between newborns and adults (17,(38)(39)(40)(41)(42)(43), but our understanding of the significant difference in disease outcomes in this population remains limited. Several promising candidates for an effective HSV vaccine have failed to show efficacy in clinical trials (44,45).…”

Section: Discussionmentioning

confidence: 99%

The Innate Immune Response to Herpes Simplex Virus 1 Infection Is Dampened in the Newborn Brain and Can Be Modulated by Exogenous Interferon Beta To Improve Survival

Giraldo

Wilcox

Longnecker

2020

mBio

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Newborns are particularly susceptible to severe forms of herpes simplex virus 1 (HSV-1) infection, including encephalitis and multisystemic disseminated disease. The underlying age-dependent differences in the immune response that explain this increased susceptibility relative to the adult population remain largely understudied. Using a murine model of HSV-1 infection, we found that newborn mice are largely susceptible to intracranial and intraperitoneal challenge while adult mice are highly resistant. This age-dependent difference correlated with differential basal-level expression of components of innate immune signaling pathways, which resulted in dampened interferon (IFN) signaling in the newborn brain. To explore the possibility of modulating the IFN response in the newborn brain to recapitulate the adult phenotype, we administered exogenous IFN-β in the context of disseminated HSV-1 infection. IFN-β treatment resulted in significantly increased survival and delayed viral neuroinvasion in the newborn. These effects were associated with changes in the type I IFN response in the brain, reduced viral replication in the periphery, and the stabilization of the blood-brain barrier (BBB). Our study reveals important age-dependent differences in the innate immune response to HSV-1 infection and suggests a contribution of the BBB and the brain parenchyma in mediating the increased susceptibility to HSV-1 infection observed in the newborn. These results could provide the basis for potential new therapeutic strategies for life-threatening HSV-1 infection in newborns. IMPORTANCE Herpes simplex virus (HSV) is a ubiquitous human pathogen affecting 50 to 80% of the population in North America and Europe. HSV infection is commonly asymptomatic in the adult population but can result in fatal encephalitis in the newborn. Current treatment with acyclovir has improved mortality in the newborn; however, severe neurologic sequelae are still a major concern following HSV encephalitis. For this reason, there is a critical need to better understand the underlying differences in the immune response between the two age groups that could be used to develop more effective treatments. In this study, we investigated differences in the innate immune response to viral infection in the brains of newborn and adult mice. We found that, similar to humans, newborn mice are more susceptible to HSV infection than the adult. Increased susceptibility was associated with dampened innate immune responses in the newborn brain that could be rescued by administering interferon beta.

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The Type I Interferon Response and Age-Dependent Susceptibility to Herpes Simplex Virus Infection

Cited by 9 publications

References 74 publications

Stem cell‐derived enteroid cultures as a tool for dissecting host‐parasite interactions in the small intestinal epithelium

Stem cell‐derived enteroid cultures as a tool for dissecting host‐parasite interactions in the small intestinal epithelium

Genome-wide DNA methylation reveals potential epigenetic mechanism of age-dependent viral susceptibility in grass carp

The Innate Immune Response to Herpes Simplex Virus 1 Infection Is Dampened in the Newborn Brain and Can Be Modulated by Exogenous Interferon Beta To Improve Survival

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