Regional astrocyte IFN signaling restricts pathogenesis during neurotropic viral infection

Daniels, Brian P.; Jujjavarapu, Harsha; Durrant, Douglas M.; Williams, J. L.; Green, Richard; White, James P.; Lazear, Helen M.; Gale, Michael; Diamond, Michael S.; Klein, Robyn S.

doi:10.1172/jci88720

Cited by 107 publications

(123 citation statements)

References 66 publications

(108 reference statements)

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“…Our data therefore suggest that type I IFN signaling within astrocytes block their infection by ZIKV and prevent BBB breakdown. The neuroprotective role of the type I IFN cascade within astrocytes has recently been ascribed during the infection of another flavivirus, West Nile virus 13 . Astrocyte-specific Ifnar1-dependence for BBB leakage in ZIKV infection should be examined in future studies.…”

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confidence: 99%

Antiviral CD8 T cells induce Zika-virus-associated paralysis in mice

et al. 2017

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Zika virus (ZIKV) is an emerging, mosquito-borne RNA virus. The rapid spread of ZIKV within the Americas has unveiled microcephaly1 and Guillain-Barré syndrome 2,3 as ZIKV-associated neurological complications. Recent reports have further indicated other neurological manifestations to be associated with ZIKV including myelitis 4, meningoencephalitis 5 and fatal encephalitis6. Here, we investigate the neuropathogenesis of ZIKV infection in IFNAR knockout (Ifnar1−/−) mice, an infection model that exhibits high viral burden within the central nervous system (CNS). We show that systemic spread of ZIKV from the site of infection to the brain requires Ifnar1-deficiency in the hematopoietic compartment. However, spread of ZIKV within the CNS is supported by Ifnar1-deficient non-hematopoietic cells. Within this context, ZIKV infection of astrocytes results in breakdown of the blood-brain barrier and a large influx of CD8+ effector T cells. Further, we find antiviral activity of CD8+ T cells within the brain markedly limits ZIKV infection of neurons, but as a consequence instigates ZIKV-associated paralysis. Taken together, our study uncovers mechanisms underlying ZIKV-neuropathogenesis within a susceptible mouse model and suggests BBB breakdown and T cell mediated neuropathology as potential underpinnings of ZIKV-associated neurological complications in humans.

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confidence: 99%

Antiviral CD8 T cells induce Zika-virus-associated paralysis in mice

et al. 2017

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“…cDNA was synthesized using oligo(dT) random hexamers and SuperScript III Reverse Transcriptase (Life Technologies). Fluorogenic quantitative reverse transcriptase PCR (qRT-PCR) analysis was performed with previously published oligonucleotide primers (Daniels et al, 2017) (Table S1) using Sybr Green reagents and a ViiA 7 Real-Time PCR System (Applied Biosystems). Cycle threshold (CT) values for analyzed cytokine/chemokine genes were normalized to CT values of the housekeeping gene Gapdh (CT Target − CT Gapdh = ΔCT) Data were subsequently normalized to baseline control values (ΔCT experimental − ΔCT control = ΔΔCT.…”

Section: Star Methodsmentioning

confidence: 99%

“…Neuroimmune control of WNV infection requires robust innate immune responses among resident CNS cells, as well as recruitment of infiltrating peripheral leukocytes (Cho and Diamond, 2012; Daniels and Klein, 2015; Suthar et al, 2013). However, CNS immune responses must be carefully regulated, as neural tissue is susceptible to immunologic injury and is limited in its capacity for repair (Daniels et al, 2017; Wang et al, 2003). Thus, uncovering the mechanisms that promote protective versus pathologic CNS inflammation during neurotropic flavivirus infection is critical for the development of targeted treatments, none of which currently exist (Kok, 2016).…”

Section: Introductionmentioning

confidence: 99%

RIPK3 Restricts Viral Pathogenesis via Cell Death-Independent Neuroinflammation

Daniels

Snyder

Olsen

et al. 2017

Cell

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140

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Summary Receptor-interacting kinase-3 (RIPK3) is an activator of necroptotic cell death, but recent work has implicated additional roles for RIPK3 in inflammatory signaling independent of cell death. However, while necroptosis has been shown to contribute to antiviral immunity, death-independent roles for RIPK3 in host defense have not been demonstrated. Using a mouse model of West Nile virus (WNV) encephalitis, we show that RIPK3 restricts WNV pathogenesis independently of cell death. Ripk3−/− mice exhibited enhanced mortality compared to WT controls, while mice lacking the necroptotic effector MLKL, or both MLKL and caspase-8, were unaffected. The enhanced susceptibility of Ripk3−/− mice arose from suppressed neuronal chemokine expression and decreased central nervous system (CNS) recruitment of T lymphocytes and inflammatory myeloid cells, while peripheral immunity remained intact. These data identify pleiotropic functions for RIPK3 in the restriction of viral pathogenesis, and implicate RIPK3 as a key coordinator of immune responses within the CNS.

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“…Researchers have found that the inflammatory chemokine osteopontin (OPN) can loosen the blood‐brain barrier in mice and promote WNV nerve invasive infection (Figure ) . The study found that interferon (IFN) signalling regulates permeability of the blood‐brain barrier after WNV infection . Some researchers have found that WNV affects the activation of the JAK‐STAT pathway by reducing the steady‐state level of tyrosine phosphorylation, antagonizing the immune response induced by IFN (Figure ) .…”

Section: Possible Mechanisms By Which Flaviviruses Penetrate the Bloomentioning

confidence: 99%

“…Researchers have begun to study glial cells. White matter astrocytes have been found to be key responders to viral infection, and ZIKV can infect astrocytes . For JEV, microglia and astrocytes, especially the primary cell types, are the more important effector cell types …”

Section: Nervous System Target Cells Infected By Flavivirusesmentioning

confidence: 99%

Research advancements in the neurological presentation of flaviviruses

Chen

Zhang

et al. 2018

Reviews in Medical Virology

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Summary Owing to the large‐scale epidemic of Zika virus disease and its association with microcephaly, properties that allow flaviviruses to cause nervous system diseases are an important area of investigation. At present, although potential pathogenic mechanisms of flaviviruses in the nervous system have been examined, they have not been completely elucidated. In this paper, we review the possible mechanisms of blood‐brain barrier penetration, the pathological effects on neurons, and the association between virus mutations and neurotoxicity. A hypothesis on neurotoxicity caused by the Zika virus is presented. Clarifying the mechanisms of virulence of flaviviruses will be helpful in finding better antiviral drugs and optimizing the treatment of symptoms.

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Regional astrocyte IFN signaling restricts pathogenesis during neurotropic viral infection

Cited by 107 publications

References 66 publications

Antiviral CD8 T cells induce Zika-virus-associated paralysis in mice

Antiviral CD8 T cells induce Zika-virus-associated paralysis in mice

RIPK3 Restricts Viral Pathogenesis via Cell Death-Independent Neuroinflammation

Research advancements in the neurological presentation of flaviviruses

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