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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

Viral titers in brain tissue at different times after IC inoculation with either HSV-1(F) (● wild-type newborns, ◆ HVEM KO newborns, ▲ nectin-1 KO newborns, * wild-type adults) or HSV-2(333) (○ wild-type newborns, ◇ HVEM KO newborns, △ nectin-1 KO newborns, + wild-type adults), in newborn mice of different genotypes or adult wild-type mice. Each symbol represents PFU per g tissue from an individual mouse, with horizontal bars indicating geometric means for each group. Symbols plotted in the gray box represent values below the detection limit of the assay. Virus was not detected in any samples from control mice inoculated in an identical manner with vehicle (PBS-GCS). Differences in titer between newborn samples for the same serotype of virus did not statistically differ based on genotype. A. Mice were sacrificed one day after inoculation (for each group of newborns, n=3–4 from a single litter). *p=0.04 vs. nectin-1 KO newborn infected with HSV-1; **p=0.05 vs. wild-type newborn infected with HSV-1. B. Mice were sacrificed two days after inoculation (for each group of newborns, n=4–9 from two separate litters). *p=0.03 vs. nectin-1 KO newborn infected with HSV-1; **p=0.002 vs. wild-type newborn infected with HSV-2, †p=0.004 vs. wild-type adult infected with HSV-1. C. Mice were sacrificed three to four days after inoculation (for each group of newborns, n=3–7 from 1–2 litters). No statistical differences were identified for replication within or between any groups.
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Figure 2: Viral titers in brain tissue at different times after IC inoculation with either HSV-1(F) (● wild-type newborns, ◆ HVEM KO newborns, ▲ nectin-1 KO newborns, * wild-type adults) or HSV-2(333) (○ wild-type newborns, ◇ HVEM KO newborns, △ nectin-1 KO newborns, + wild-type adults), in newborn mice of different genotypes or adult wild-type mice. Each symbol represents PFU per g tissue from an individual mouse, with horizontal bars indicating geometric means for each group. Symbols plotted in the gray box represent values below the detection limit of the assay. Virus was not detected in any samples from control mice inoculated in an identical manner with vehicle (PBS-GCS). Differences in titer between newborn samples for the same serotype of virus did not statistically differ based on genotype. A. Mice were sacrificed one day after inoculation (for each group of newborns, n=3–4 from a single litter). *p=0.04 vs. nectin-1 KO newborn infected with HSV-1; **p=0.05 vs. wild-type newborn infected with HSV-1. B. Mice were sacrificed two days after inoculation (for each group of newborns, n=4–9 from two separate litters). *p=0.03 vs. nectin-1 KO newborn infected with HSV-1; **p=0.002 vs. wild-type newborn infected with HSV-2, †p=0.004 vs. wild-type adult infected with HSV-1. C. Mice were sacrificed three to four days after inoculation (for each group of newborns, n=3–7 from 1–2 litters). No statistical differences were identified for replication within or between any groups.

Mentions: Differences in mortality between groups of newborn mice inoculated IC with different serotypes of HSV could be explained by relative differences in the ability of the viruses to replicate in brain tissue. To assess HSV replication over time in brains of newborn mice, we inoculated separate groups of seven-day-old mice with either HSV-1(F) or HSV-2(333), euthanized them at different times after inoculation, and performed plaque assays on homogenates of brain tissue. A general trend of higher HSV-1 replication relative to HSV-2 was observed in all genotypes; however, we found no statistical differences in viral titer in WT or HVEM KO newborns when comparing replication of HSV-1 with HSV-2 over the first two days after inoculation (Figure 2A-B). In nectin-1 KO newborns, there was a statistical difference in titer on both days (p<0.05), with HSV-1 replication higher than HSV-2. Replication of HSV-1 and HSV-2 was also statistically similar when comparing HVEM KO and nectin-1 KO newborns with WT newborns the first two days after infection. In comparison, viral replication in brains of adult WT mice (inoculated with a higher amount of virus) led to generally lower mean titers relative to WT newborns, with statistically significant differences detected for HSV-1 on day 1 and HSV-2 on day 2.


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)

Viral titers in brain tissue at different times after IC inoculation with either HSV-1(F) (● wild-type newborns, ◆ HVEM KO newborns, ▲ nectin-1 KO newborns, * wild-type adults) or HSV-2(333) (○ wild-type newborns, ◇ HVEM KO newborns, △ nectin-1 KO newborns, + wild-type adults), in newborn mice of different genotypes or adult wild-type mice. Each symbol represents PFU per g tissue from an individual mouse, with horizontal bars indicating geometric means for each group. Symbols plotted in the gray box represent values below the detection limit of the assay. Virus was not detected in any samples from control mice inoculated in an identical manner with vehicle (PBS-GCS). Differences in titer between newborn samples for the same serotype of virus did not statistically differ based on genotype. A. Mice were sacrificed one day after inoculation (for each group of newborns, n=3–4 from a single litter). *p=0.04 vs. nectin-1 KO newborn infected with HSV-1; **p=0.05 vs. wild-type newborn infected with HSV-1. B. Mice were sacrificed two days after inoculation (for each group of newborns, n=4–9 from two separate litters). *p=0.03 vs. nectin-1 KO newborn infected with HSV-1; **p=0.002 vs. wild-type newborn infected with HSV-2, †p=0.004 vs. wild-type adult infected with HSV-1. C. Mice were sacrificed three to four days after inoculation (for each group of newborns, n=3–7 from 1–2 litters). No statistical differences were identified for replication within or between any groups.
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Figure 2: Viral titers in brain tissue at different times after IC inoculation with either HSV-1(F) (● wild-type newborns, ◆ HVEM KO newborns, ▲ nectin-1 KO newborns, * wild-type adults) or HSV-2(333) (○ wild-type newborns, ◇ HVEM KO newborns, △ nectin-1 KO newborns, + wild-type adults), in newborn mice of different genotypes or adult wild-type mice. Each symbol represents PFU per g tissue from an individual mouse, with horizontal bars indicating geometric means for each group. Symbols plotted in the gray box represent values below the detection limit of the assay. Virus was not detected in any samples from control mice inoculated in an identical manner with vehicle (PBS-GCS). Differences in titer between newborn samples for the same serotype of virus did not statistically differ based on genotype. A. Mice were sacrificed one day after inoculation (for each group of newborns, n=3–4 from a single litter). *p=0.04 vs. nectin-1 KO newborn infected with HSV-1; **p=0.05 vs. wild-type newborn infected with HSV-1. B. Mice were sacrificed two days after inoculation (for each group of newborns, n=4–9 from two separate litters). *p=0.03 vs. nectin-1 KO newborn infected with HSV-1; **p=0.002 vs. wild-type newborn infected with HSV-2, †p=0.004 vs. wild-type adult infected with HSV-1. C. Mice were sacrificed three to four days after inoculation (for each group of newborns, n=3–7 from 1–2 litters). No statistical differences were identified for replication within or between any groups.
Mentions: Differences in mortality between groups of newborn mice inoculated IC with different serotypes of HSV could be explained by relative differences in the ability of the viruses to replicate in brain tissue. To assess HSV replication over time in brains of newborn mice, we inoculated separate groups of seven-day-old mice with either HSV-1(F) or HSV-2(333), euthanized them at different times after inoculation, and performed plaque assays on homogenates of brain tissue. A general trend of higher HSV-1 replication relative to HSV-2 was observed in all genotypes; however, we found no statistical differences in viral titer in WT or HVEM KO newborns when comparing replication of HSV-1 with HSV-2 over the first two days after inoculation (Figure 2A-B). In nectin-1 KO newborns, there was a statistical difference in titer on both days (p<0.05), with HSV-1 replication higher than HSV-2. Replication of HSV-1 and HSV-2 was also statistically similar when comparing HVEM KO and nectin-1 KO newborns with WT newborns the first two days after infection. In comparison, viral replication in brains of adult WT mice (inoculated with a higher amount of virus) led to generally lower mean titers relative to WT newborns, with statistically significant differences detected for HSV-1 on day 1 and HSV-2 on day 2.

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