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Neuronal Interferon Signaling Is Required for Protection against Herpes Simplex Virus Replication and Pathogenesis.

Rosato PC, Leib DA - PLoS Pathog. (2015)

Bottom Line: Compartmentalized neuron cultures revealed that mature sensory neurons respond to IFNβ at both the axon and cell body through distinct mechanisms, resulting in control of HSV-1.Furthermore, neurovirulence was restored to an HSV strain lacking the IFN-modulating gene, γ34.5, despite its expected attenuation in peripheral tissues.These studies define a crucial role for neuronal IFN signaling for protection against HSV-1 pathogenesis and replication, and they provide a novel framework to enhance our understanding of the interface between host innate immunity and neurotropic pathogens.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire, United States of America.

ABSTRACT
Interferon (IFN) responses are critical for controlling herpes simplex virus 1 (HSV-1). The importance of neuronal IFN signaling in controlling acute and latent HSV-1 infection remains unclear. Compartmentalized neuron cultures revealed that mature sensory neurons respond to IFNβ at both the axon and cell body through distinct mechanisms, resulting in control of HSV-1. Mice specifically lacking neural IFN signaling succumbed rapidly to HSV-1 corneal infection, demonstrating that IFN responses of the immune system and non-neuronal tissues are insufficient to confer survival following virus challenge. Furthermore, neurovirulence was restored to an HSV strain lacking the IFN-modulating gene, γ34.5, despite its expected attenuation in peripheral tissues. These studies define a crucial role for neuronal IFN signaling for protection against HSV-1 pathogenesis and replication, and they provide a novel framework to enhance our understanding of the interface between host innate immunity and neurotropic pathogens.

No MeSH data available.


Related in: MedlinePlus

Neural STAT1 expression is critical for controlling HSV-1 replication in vivo.Viral titers in the TG, brain stem and brain of Stat1N-/- or Stat1fl/fl mice infected via corneal scarification with 2 x 106 PFU/eye WT (strain 17) or Δγ34.5 virus. Viral titers were measured at 3 dpi (A) and 5 dpi (B). Dashed lines represent the limit of detection. Error bars represent SEM of a minimum of 13 mice total over 2 experiments. Two-way ANOVA was performed where ** p<0.01, ***p<0.001.
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ppat.1005028.g004: Neural STAT1 expression is critical for controlling HSV-1 replication in vivo.Viral titers in the TG, brain stem and brain of Stat1N-/- or Stat1fl/fl mice infected via corneal scarification with 2 x 106 PFU/eye WT (strain 17) or Δγ34.5 virus. Viral titers were measured at 3 dpi (A) and 5 dpi (B). Dashed lines represent the limit of detection. Error bars represent SEM of a minimum of 13 mice total over 2 experiments. Two-way ANOVA was performed where ** p<0.01, ***p<0.001.

Mentions: To examine virus replication in the nervous system, we next infected Stat1N-/- and Stat1fl/fl mice corneally with WT or Δγ34.5 viruses then measured titers in the TG, brain stem and brain. There was a significant increase in WT titers in the TGs of infected Stat1N-/- compared to Stat1fl/fl mice (Fig 4A and 4B). Additionally, Δγ34.5 titers in the TGs of Stat1N-/- mice were significantly increased by ~100-fold on both days almost achieving the titers of WT virus. On day 3, low levels of virus were observed in the brain stem and notably there were no differences in the titers between Stat1N-/- and Stat1fl/fl mice (Fig 4A). No virus was detected in the brain at this timepoint. On day 5, however, significant increases in WT viral titers were observed in brain stems and brains of Stat1N-/- mice compared to Stat1fl/fl (Fig 4B). Moreover, we saw large increases in Δγ34.5 titers in the brain stems and brains of Stat1N-/- mice, with low titers in littermate controls (Fig 4B). Together, these data show that neuronal STAT1 expression is critical for controlling HSV-1 replication in nervous tissue and that ICP34.5 counters this STAT1-driven response.


Neuronal Interferon Signaling Is Required for Protection against Herpes Simplex Virus Replication and Pathogenesis.

Rosato PC, Leib DA - PLoS Pathog. (2015)

Neural STAT1 expression is critical for controlling HSV-1 replication in vivo.Viral titers in the TG, brain stem and brain of Stat1N-/- or Stat1fl/fl mice infected via corneal scarification with 2 x 106 PFU/eye WT (strain 17) or Δγ34.5 virus. Viral titers were measured at 3 dpi (A) and 5 dpi (B). Dashed lines represent the limit of detection. Error bars represent SEM of a minimum of 13 mice total over 2 experiments. Two-way ANOVA was performed where ** p<0.01, ***p<0.001.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4495997&req=5

ppat.1005028.g004: Neural STAT1 expression is critical for controlling HSV-1 replication in vivo.Viral titers in the TG, brain stem and brain of Stat1N-/- or Stat1fl/fl mice infected via corneal scarification with 2 x 106 PFU/eye WT (strain 17) or Δγ34.5 virus. Viral titers were measured at 3 dpi (A) and 5 dpi (B). Dashed lines represent the limit of detection. Error bars represent SEM of a minimum of 13 mice total over 2 experiments. Two-way ANOVA was performed where ** p<0.01, ***p<0.001.
Mentions: To examine virus replication in the nervous system, we next infected Stat1N-/- and Stat1fl/fl mice corneally with WT or Δγ34.5 viruses then measured titers in the TG, brain stem and brain. There was a significant increase in WT titers in the TGs of infected Stat1N-/- compared to Stat1fl/fl mice (Fig 4A and 4B). Additionally, Δγ34.5 titers in the TGs of Stat1N-/- mice were significantly increased by ~100-fold on both days almost achieving the titers of WT virus. On day 3, low levels of virus were observed in the brain stem and notably there were no differences in the titers between Stat1N-/- and Stat1fl/fl mice (Fig 4A). No virus was detected in the brain at this timepoint. On day 5, however, significant increases in WT viral titers were observed in brain stems and brains of Stat1N-/- mice compared to Stat1fl/fl (Fig 4B). Moreover, we saw large increases in Δγ34.5 titers in the brain stems and brains of Stat1N-/- mice, with low titers in littermate controls (Fig 4B). Together, these data show that neuronal STAT1 expression is critical for controlling HSV-1 replication in nervous tissue and that ICP34.5 counters this STAT1-driven response.

Bottom Line: Compartmentalized neuron cultures revealed that mature sensory neurons respond to IFNβ at both the axon and cell body through distinct mechanisms, resulting in control of HSV-1.Furthermore, neurovirulence was restored to an HSV strain lacking the IFN-modulating gene, γ34.5, despite its expected attenuation in peripheral tissues.These studies define a crucial role for neuronal IFN signaling for protection against HSV-1 pathogenesis and replication, and they provide a novel framework to enhance our understanding of the interface between host innate immunity and neurotropic pathogens.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire, United States of America.

ABSTRACT
Interferon (IFN) responses are critical for controlling herpes simplex virus 1 (HSV-1). The importance of neuronal IFN signaling in controlling acute and latent HSV-1 infection remains unclear. Compartmentalized neuron cultures revealed that mature sensory neurons respond to IFNβ at both the axon and cell body through distinct mechanisms, resulting in control of HSV-1. Mice specifically lacking neural IFN signaling succumbed rapidly to HSV-1 corneal infection, demonstrating that IFN responses of the immune system and non-neuronal tissues are insufficient to confer survival following virus challenge. Furthermore, neurovirulence was restored to an HSV strain lacking the IFN-modulating gene, γ34.5, despite its expected attenuation in peripheral tissues. These studies define a crucial role for neuronal IFN signaling for protection against HSV-1 pathogenesis and replication, and they provide a novel framework to enhance our understanding of the interface between host innate immunity and neurotropic pathogens.

No MeSH data available.


Related in: MedlinePlus