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Herpes simplex virus serotype and entry receptor availability alter CNS disease in a mouse model of neonatal HSV.

Kopp SJ, Ranaivo HR, Wilcox DR, Karaba AH, Wainwright MS, Muller WJ - Pediatr. Res. (2014)

Bottom Line: Prior studies have shown receptor-dependent differences in pathogenesis that depend on route of inoculation and host developmental age.In this regard, significantly greater amounts of inflammatory mediators were detected in brain homogenates from WT newborns 2 d after infection compared with adults and receptor-knockout newborns.Dysregulation of inflammatory responses induced by infection may influence the severity of HSV encephalitis.

View Article: PubMed Central - PubMed

Affiliation: 1] Department of Microbiology-Immunology, Northwestern University Feinberg School of Medicine, Chicago, Illinois [2] Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, Illinois.

ABSTRACT

Background: Outcomes of neonates with herpes simplex virus (HSV) encephalitis are worse after infection with HSV-2 when compared with HSV-1. The proteins herpes virus entry mediator (HVEM) and nectin-1 mediate HSV entry into susceptible cells. Prior studies have shown receptor-dependent differences in pathogenesis that depend on route of inoculation and host developmental age.

Methods: We investigated serotype-related differences in HSV disease and their relationship to entry receptor availability in a mouse model of encephalitis.

Results: Mortality was attenuated in 7-d-old, wild-type (WT) mice inoculated with HSV-1(F) when compared with HSV-2(333). No serotype-specific differences were seen after inoculation of adult mice. HSV-1 pathogenesis was also attenuated relative to HSV-2 in newborn but not adult mice lacking HVEM or nectin-1. HSV-2 requires nectin-1 for encephalitis in adult but not newborn mice; in contrast, nectin-1 was important for HSV-1 pathogenesis in both age groups. Early viral replication was independent of age, viral serotype, or mouse genotype, suggesting host responses influence outcomes. In this regard, significantly greater amounts of inflammatory mediators were detected in brain homogenates from WT newborns 2 d after infection compared with adults and receptor-knockout newborns.

Conclusion: Dysregulation of inflammatory responses induced by infection may influence the severity of HSV encephalitis.

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Related in: MedlinePlus

Chemokine levels in brain homogenates two days after IC inoculation with either HSV-1(F) (gray bars) or HSV-2(333) (black bars), in newborn mice of different genotypes or adult wild-type mice. Bars represent mean pg/g brain tissue from agroup of mice, with standard deviations indicated. *p<0.05 when compared with HSV-1 infection of WT newborns. †p<0.05 when compared with HSV-2 infection of WT newborns. Each group of newborn mice included 2–3 separate litters and 4–7 mice. A. IL-1β. B. IFN-γ . C. IL-6. D. KC/Gro.
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Figure 3: Chemokine levels in brain homogenates two days after IC inoculation with either HSV-1(F) (gray bars) or HSV-2(333) (black bars), in newborn mice of different genotypes or adult wild-type mice. Bars represent mean pg/g brain tissue from agroup of mice, with standard deviations indicated. *p<0.05 when compared with HSV-1 infection of WT newborns. †p<0.05 when compared with HSV-2 infection of WT newborns. Each group of newborn mice included 2–3 separate litters and 4–7 mice. A. IL-1β. B. IFN-γ . C. IL-6. D. KC/Gro.

Mentions: The lack of correlation between mortality and viral replication after IC inoculation of newborn mice suggested that differences in host responses in the brain might contribute to differences in pathogenesis. Prior in vitro studies reported that cells obtained from newborns generated diminished amounts of type I interferons (IFNs) in response to HSV when compared with cells from adults (21), and additional evidence in the literature suggests that the generation of type I IFNs is more effectively suppressed by HSV-2 than HSV-l strains (22, 23). We applied a multiplex ELISA assay to measure the production of different inflammatory mediators in brain tissue of infected mice two days after inoculation. We noted significantly higher levels of both IL-1β (Figure 3A) and IFN-γ (Figure 3B) in brain tissue from WT newborns infected with HSV-1 when compared with tissue from WT newborns infected with HSV-2. Serotype-related differences in these and other inflammatory mediators were not observed when comparing similarly inoculated receptor KO newborns or adult mice, likely attributable to the overall low levels detected in these samples.


Herpes simplex virus serotype and entry receptor availability alter CNS disease in a mouse model of neonatal HSV.

Kopp SJ, Ranaivo HR, Wilcox DR, Karaba AH, Wainwright MS, Muller WJ - Pediatr. Res. (2014)

Chemokine levels in brain homogenates two days after IC inoculation with either HSV-1(F) (gray bars) or HSV-2(333) (black bars), in newborn mice of different genotypes or adult wild-type mice. Bars represent mean pg/g brain tissue from agroup of mice, with standard deviations indicated. *p<0.05 when compared with HSV-1 infection of WT newborns. †p<0.05 when compared with HSV-2 infection of WT newborns. Each group of newborn mice included 2–3 separate litters and 4–7 mice. A. IL-1β. B. IFN-γ . C. IL-6. D. KC/Gro.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4233006&req=5

Figure 3: Chemokine levels in brain homogenates two days after IC inoculation with either HSV-1(F) (gray bars) or HSV-2(333) (black bars), in newborn mice of different genotypes or adult wild-type mice. Bars represent mean pg/g brain tissue from agroup of mice, with standard deviations indicated. *p<0.05 when compared with HSV-1 infection of WT newborns. †p<0.05 when compared with HSV-2 infection of WT newborns. Each group of newborn mice included 2–3 separate litters and 4–7 mice. A. IL-1β. B. IFN-γ . C. IL-6. D. KC/Gro.
Mentions: The lack of correlation between mortality and viral replication after IC inoculation of newborn mice suggested that differences in host responses in the brain might contribute to differences in pathogenesis. Prior in vitro studies reported that cells obtained from newborns generated diminished amounts of type I interferons (IFNs) in response to HSV when compared with cells from adults (21), and additional evidence in the literature suggests that the generation of type I IFNs is more effectively suppressed by HSV-2 than HSV-l strains (22, 23). We applied a multiplex ELISA assay to measure the production of different inflammatory mediators in brain tissue of infected mice two days after inoculation. We noted significantly higher levels of both IL-1β (Figure 3A) and IFN-γ (Figure 3B) in brain tissue from WT newborns infected with HSV-1 when compared with tissue from WT newborns infected with HSV-2. Serotype-related differences in these and other inflammatory mediators were not observed when comparing similarly inoculated receptor KO newborns or adult mice, likely attributable to the overall low levels detected in these samples.

Bottom Line: Prior studies have shown receptor-dependent differences in pathogenesis that depend on route of inoculation and host developmental age.In this regard, significantly greater amounts of inflammatory mediators were detected in brain homogenates from WT newborns 2 d after infection compared with adults and receptor-knockout newborns.Dysregulation of inflammatory responses induced by infection may influence the severity of HSV encephalitis.

View Article: PubMed Central - PubMed

Affiliation: 1] Department of Microbiology-Immunology, Northwestern University Feinberg School of Medicine, Chicago, Illinois [2] Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, Illinois.

ABSTRACT

Background: Outcomes of neonates with herpes simplex virus (HSV) encephalitis are worse after infection with HSV-2 when compared with HSV-1. The proteins herpes virus entry mediator (HVEM) and nectin-1 mediate HSV entry into susceptible cells. Prior studies have shown receptor-dependent differences in pathogenesis that depend on route of inoculation and host developmental age.

Methods: We investigated serotype-related differences in HSV disease and their relationship to entry receptor availability in a mouse model of encephalitis.

Results: Mortality was attenuated in 7-d-old, wild-type (WT) mice inoculated with HSV-1(F) when compared with HSV-2(333). No serotype-specific differences were seen after inoculation of adult mice. HSV-1 pathogenesis was also attenuated relative to HSV-2 in newborn but not adult mice lacking HVEM or nectin-1. HSV-2 requires nectin-1 for encephalitis in adult but not newborn mice; in contrast, nectin-1 was important for HSV-1 pathogenesis in both age groups. Early viral replication was independent of age, viral serotype, or mouse genotype, suggesting host responses influence outcomes. In this regard, significantly greater amounts of inflammatory mediators were detected in brain homogenates from WT newborns 2 d after infection compared with adults and receptor-knockout newborns.

Conclusion: Dysregulation of inflammatory responses induced by infection may influence the severity of HSV encephalitis.

Show MeSH
Related in: MedlinePlus