The Astrocyte Type I Interferon Response Is Essential for Protection against Herpes Simplex Encephalitis

Hayes, Cooper K.; Giraldo, Daniel; Wilcox, Douglas R.; Longnecker, Richard

doi:10.1128/jvi.01783-21

Cited by 3 publications

(2 citation statements)

References 9 publications

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“…Thus, it is most likely that virus antigens released from infected neurons or astrocytes activate adjacent microglial cells to stimulate production of chemokines and cytokines that then serve to recruit antiviral NK cells and T cells as well as augment IFNγ production to further control virus infection. While microglia have been studied extensively in the context of the innate immune response to HSV1 infection, recent work also demonstrates that crosstalk between microglia and astrocytes plays an important role in controlling HSV1 replication and neuroinflammation [ 53 ]. The relative importance of different CNS cell populations in eliciting RIPK3/RIPK1-FADD-Caspase 8 complex-mediated signaling during HSE neuropathogenesis therefore deserves further investigation.…”

Section: Discussionmentioning

confidence: 99%

RIPK3 and caspase 8 collaborate to limit herpes simplex encephalitis

et al. 2022

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Invasion of the brain by herpes simplex virus 1 (HSV1) can lead to the development of herpes simplex encephalitis (HSE) that is often associated with significant morbidity and mortality regardless of therapeutic intervention. Both virus and host immune factors dictate HSE onset and progression. Because programmed cell death pathways including necroptosis are important antiviral defense mechanisms in HSV-1-associated peripheral diseases, they might also play critical roles in HSV1 neuropathogenesis. HSV1-encoded ICP6 prevents receptor-interacting protein kinase 3 (RIPK3)-mediated necroptosis during infection of human cells, but it also acts as a species-dependent inducer of necroptosis in murine cells and thereby restricts virus replication. We therefore used an established mouse model of HSE to investigate RIPK3-mediated necroptosis impact on HSV1 neuropathogenesis. Following corneal HSV1 inoculation, RIPK3 knockout mice showed increased susceptibility to HSE when compared with wildtype mice indicating RIPK3 helps to limit HSE progression. RIPK3-mediated defense against HSE was found to be independent of the kinase domain necessary to drive necroptosis implicating that a death independent function of RIPK3 protects against HSE. Conversely the pro-necroptotic kinase function RIPK3 served to limit viral replication in corneal tissue implicating a tissue-specific RIPK3 function in limiting HSV-1. Further evaluation of the kinase-independent mechanism to restrict HSE revealed that the RIPK3 signaling partner, caspase 8, contributes to limiting HSE neuropathogenesis. Increased HSE susceptibility from loss of caspase 8 and RIPK3 correlated with decreased levels of chemokines, cytokines, and antiviral lymphocytes recruitment to the brain. We conclude that RIPK3 contributes toward host control of HSV1 replication in a tissue-specific fashion. Whereas RIPK3-mediated necroptosis restricts virus replication within the cornea, kinase-independent induction of inflammation by RIPK3 in collaboration with caspase 8 restricts virus replication within the brain during HSE neuropathogenesis.

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Section: Discussionmentioning

confidence: 99%

RIPK3 and caspase 8 collaborate to limit herpes simplex encephalitis

et al. 2022

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“…For example, IFNAR signaling in cerebellar astrocytes leads to an decrease in BBB permeability after intracranial inoculation of West Nile virus (Daniels et al, 2017). Astrocytic type I interferon signaling is also necessary to activate microglia and recruit peripheral immune cells after vesicular stomatitis virus (Chhatbar et al, 2018), and is critical for protection and herpesvirus encephalitis (Hayes et al, 2022). Similarly, interferon lambda (IFNλ) signaling via the interferon lambda receptor (IFNLR1) is critical for BBB integrity during WNV infection (Lazear et al, 2015), but the role astrocytes play in this signaling pathway has not yet been fully elucidated.…”

Section: Astrocytes Regulate the Blood-brain Barrier And Respond To V...mentioning

confidence: 99%

The multitaskers of the brain: Glial responses to viral infections and associated post‐infectious neurologic sequelae

Davé¹,

Klein

2022

Glia

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Many viral infections cause acute and chronic neurologic diseases which can lead to degeneration of cortical functions. While neurotropic viruses that gain access to the central nervous system (CNS) may induce brain injury directly via infection of neurons or their supporting cells, they also alter brain function via indirect neuroimmune mechanisms that may disrupt the blood-brain barrier (BBB), eliminate synapses, and generate neurotoxic astrocytes and microglia that prevent recovery of neuronal circuits. Non-neuroinvasive, neurovirulent viruses may also trigger aberrant responses in glial cells, including those that interfere with motor and sensory behaviors, encoding of memories and executive function. Increasing evidence from human and animal studies indicate that neuroprotective antiviral responses that amplify levels of innate immune molecules dysregulate normal neuroimmune processes, even in the absence of neuroinvasion, which may persist after virus is cleared. In this review, we discuss how select emerging and re-emerging RNA viruses induce neuroimmunologic responses that lead to dysfunction of higher order processes including visuospatial recognition, learning and memory, and motor control. Identifying therapeutic targets that return the neuroimmune system to homeostasis is critical for preventing virusinduced neurodegenerative disorders.

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Temporally resolved single-cell RNA sequencing reveals protective and pathological responses during herpes simplex virus 1 CNS infection

Ding,

Lai,

Klæstrup

et al. 2024

Preprint

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Herpes Simplex Virus 1 (HSV-1) is a common human neurotropic virus with the majority of adults harboring latent-recurrent infections. In rare cases, HSV-1 infection can access the central nervous system through the neuronal route and develop into life-threatening encephalitis. Here, we used a mouse model for HSV-1 infection to describe the transcriptomic profile of the infected brain stem at the single-cell level and with temporal resolution. Among resident brain cells, microglia increased in proportion during the course of infection, while astrocytes, pericytes, and endothelial cell levels decrease. At the levels of peripheral immune cells, we found notably monocytes to strongly influx the infected brain. Large dynamic changes were found in the abundance of subpopulations of the different cell types following virus infection. For instance, we identify one subpopulation of microglia exhibiting very high type I interferon and chemokine expression early during infection. This population was also enriched for viral transcripts, suggesting localization at foci of infection, and orchestrating recruitment of other immune cells. In contrast, for the infiltrating monocytes, we identified a larger panel of unique subpopulations with antiviral and inflammatory phenotypes, and found not all of these being highly positive for viral transcripts, thus indicating monocyte activities beyond the infected brain areas. Finally, investigation of endothelial cell cross-talk with other cell types revealed that cytokines derived from microglia and monocyte, but also T cells, contribute to disturbance of the blood brain barrier. Our work thus reveals for the first time the complex nature of the cellular response in the virus-infected brain, which seeks to eliminate infection but can also prime for pathological changes.

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The Astrocyte Type I Interferon Response Is Essential for Protection against Herpes Simplex Encephalitis

Abstract: Innate immune activation by central nervous system (CNS) resident cells is critical for controlling HSV-1 replication.…

Cited by 3 publications

References 9 publications

RIPK3 and caspase 8 collaborate to limit herpes simplex encephalitis

RIPK3 and caspase 8 collaborate to limit herpes simplex encephalitis

The multitaskers of the brain: Glial responses to viral infections and associated post‐infectious neurologic sequelae

Temporally resolved single-cell RNA sequencing reveals protective and pathological responses during herpes simplex virus 1 CNS infection

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