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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

Viral zosteriform spread and pathogenesis in non-neuronal tissues of Stat1N-/- mice.A) Periocular disease in Stat1N-/- or Stat1fl/fl mice infected via the cornea with 2 x 106 PFU/eye WT (strain 17) or Δγ34.5 virus. Disease scoring was based on a 1–4 scale. B) Titers of periocular skin from Stat1N-/- or Stat1fl/fl mice infected as in (A). Data points represent the average of 2 skin punch titers from each eye. Dashed lines delineate the limit of detection, and error bars represent SEM of a minimum 12 mice, over at least 2 experiments. Two-way ANOVA was performed where one symbol indicates p<0.05, two symbols p<0.01, and three symbols p<0.001. Unless noted with brackets, * indicates significant differences between Stat1N-/- WT and Stat1N-/- Δγ34.5; # between Stat1fl/fl WT and Stat1N-/- Δγ34.5; and † between Stat1fl/fl Δγ34.5 and Stat1N-/- Δγ34.5.
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ppat.1005028.g006: Viral zosteriform spread and pathogenesis in non-neuronal tissues of Stat1N-/- mice.A) Periocular disease in Stat1N-/- or Stat1fl/fl mice infected via the cornea with 2 x 106 PFU/eye WT (strain 17) or Δγ34.5 virus. Disease scoring was based on a 1–4 scale. B) Titers of periocular skin from Stat1N-/- or Stat1fl/fl mice infected as in (A). Data points represent the average of 2 skin punch titers from each eye. Dashed lines delineate the limit of detection, and error bars represent SEM of a minimum 12 mice, over at least 2 experiments. Two-way ANOVA was performed where one symbol indicates p<0.05, two symbols p<0.01, and three symbols p<0.001. Unless noted with brackets, * indicates significant differences between Stat1N-/- WT and Stat1N-/- Δγ34.5; # between Stat1fl/fl WT and Stat1N-/- Δγ34.5; and † between Stat1fl/fl Δγ34.5 and Stat1N-/- Δγ34.5.

Mentions: Zosteriform spread involves the retrograde transport of virus from infected mucosae via the peripheral nerves to the TG, followed by anterograde transport to innervated tissue distal to the site of initial infection [1]. Following corneal infection in the mouse and in humans, periocular skin infection and disease are likely a consequence of zosteriform spread of the virus rather than direct spread from the cornea, which is dependent on robust replication in the innervating TG [41]. Based on this model, our observed pattern of viral titers in the TG predicts that WT virus would cause significantly more periocular infection and disease than Δγ34.5 in Stat1fl/fl mice, and this should be normalized in Stat1N-/- mice, despite the presence of STAT1-dependent responses in the skin. Consistent with this hypothesis, we observed significantly more periocular disease in Stat1fl/fl mice infected with WT virus compared to Δγ34.5 (Fig 6A). Furthermore, there was significantly more disease in Δγ34.5 infected Stat1N-/- mice compared to Stat1fl/fl mice, with disease levels approaching those seen in WT virus-infected mice. While this significantly increased and overt disease was in contrast to the low levels of Δγ34.5 virus (<10pfu) in corneal swabs of the Stat1N-/- mice (Fig 3B), it correlated with a significant increase in skin titers on day 5 (Fig 6B). These data therefore suggest that the lack of neural IFN-signaling causing increased replication in the TG of Stat1N-/- mice promotes periocular disease due to zosteriform spread of HSV-1. These data therefore further validate the zosteriform spread model and the phenotype of Stat1N-/- mice [41].


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

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

Viral zosteriform spread and pathogenesis in non-neuronal tissues of Stat1N-/- mice.A) Periocular disease in Stat1N-/- or Stat1fl/fl mice infected via the cornea with 2 x 106 PFU/eye WT (strain 17) or Δγ34.5 virus. Disease scoring was based on a 1–4 scale. B) Titers of periocular skin from Stat1N-/- or Stat1fl/fl mice infected as in (A). Data points represent the average of 2 skin punch titers from each eye. Dashed lines delineate the limit of detection, and error bars represent SEM of a minimum 12 mice, over at least 2 experiments. Two-way ANOVA was performed where one symbol indicates p<0.05, two symbols p<0.01, and three symbols p<0.001. Unless noted with brackets, * indicates significant differences between Stat1N-/- WT and Stat1N-/- Δγ34.5; # between Stat1fl/fl WT and Stat1N-/- Δγ34.5; and † between Stat1fl/fl Δγ34.5 and Stat1N-/- Δγ34.5.
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Related In: Results  -  Collection

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ppat.1005028.g006: Viral zosteriform spread and pathogenesis in non-neuronal tissues of Stat1N-/- mice.A) Periocular disease in Stat1N-/- or Stat1fl/fl mice infected via the cornea with 2 x 106 PFU/eye WT (strain 17) or Δγ34.5 virus. Disease scoring was based on a 1–4 scale. B) Titers of periocular skin from Stat1N-/- or Stat1fl/fl mice infected as in (A). Data points represent the average of 2 skin punch titers from each eye. Dashed lines delineate the limit of detection, and error bars represent SEM of a minimum 12 mice, over at least 2 experiments. Two-way ANOVA was performed where one symbol indicates p<0.05, two symbols p<0.01, and three symbols p<0.001. Unless noted with brackets, * indicates significant differences between Stat1N-/- WT and Stat1N-/- Δγ34.5; # between Stat1fl/fl WT and Stat1N-/- Δγ34.5; and † between Stat1fl/fl Δγ34.5 and Stat1N-/- Δγ34.5.
Mentions: Zosteriform spread involves the retrograde transport of virus from infected mucosae via the peripheral nerves to the TG, followed by anterograde transport to innervated tissue distal to the site of initial infection [1]. Following corneal infection in the mouse and in humans, periocular skin infection and disease are likely a consequence of zosteriform spread of the virus rather than direct spread from the cornea, which is dependent on robust replication in the innervating TG [41]. Based on this model, our observed pattern of viral titers in the TG predicts that WT virus would cause significantly more periocular infection and disease than Δγ34.5 in Stat1fl/fl mice, and this should be normalized in Stat1N-/- mice, despite the presence of STAT1-dependent responses in the skin. Consistent with this hypothesis, we observed significantly more periocular disease in Stat1fl/fl mice infected with WT virus compared to Δγ34.5 (Fig 6A). Furthermore, there was significantly more disease in Δγ34.5 infected Stat1N-/- mice compared to Stat1fl/fl mice, with disease levels approaching those seen in WT virus-infected mice. While this significantly increased and overt disease was in contrast to the low levels of Δγ34.5 virus (<10pfu) in corneal swabs of the Stat1N-/- mice (Fig 3B), it correlated with a significant increase in skin titers on day 5 (Fig 6B). These data therefore suggest that the lack of neural IFN-signaling causing increased replication in the TG of Stat1N-/- mice promotes periocular disease due to zosteriform spread of HSV-1. These data therefore further validate the zosteriform spread model and the phenotype of Stat1N-/- mice [41].

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