Zika virus-induced TNF-α signaling dysregulates expression of neurologic genes associated with psychiatric disorders

Kung, Po-Lun; Chou, Tsui-Wen; Lindman, Marissa; Chang, Nydia P; Buckley, B. D.; Atkins, Colm; Daniels, Brian P.

doi:10.1101/2021.11.15.468744

Cited by 2 publications

(2 citation statements)

References 119 publications

(73 reference statements)

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“…Total RNA from harvested tissues was extracted using Zymo Direct-zol RNA Miniprep kit, as per manufacturer instructions (Zymo, #R2051). Total RNA extraction from cultured cells, cDNA synthesis, and subsequent qRT-PCR were performed as previously described (22, 53). Cycle threshold (CT) values for analyzed genes were normalized to CT values of the housekeeping gene 18 S (CT Target – CT 18S = ΔCT).…”

Section: Methodsmentioning

confidence: 99%

RIPK3 promotes brain region-specific interferon signaling and restriction of tick-borne flavivirus infection

Lindman

Angel

Estevez

et al. 2023

Preprint

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Innate immune signaling in the central nervous system (CNS) exhibits many remarkable specializations that vary across cell types and CNS regions. In the setting of neuroinvasive flavivirus infection, neurons employ the immunologic kinase receptor-interacting kinase 3 (RIPK3) to promote an antiviral transcriptional program, independently of the traditional function of this enzyme in promoting necroptotic cell death. However, while recent work has established roles for neuronal RIPK3 signaling in controlling mosquito-borne flavivirus infections, including West Nile virus and Zika virus, functions for RIPK3 signaling in the CNS during tick-borne flavivirus infection have not yet been explored. Here, we use a model of Langat virus (LGTV) encephalitis to show that RIPK3 signaling is specifically required in neurons of the cerebellum to control LGTV replication and restrict disease pathogenesis. This effect did not require the necroptotic executioner molecule mixed lineage kinase domain like protein (MLKL), a finding similar to previous observations in models of mosquito-borne flavivirus infection. However, control of LGTV infection required a unique, region-specific dependence on RIPK3 to promote expression of key antiviral interferon-stimulated genes (ISG) in the cerebellum. This RIPK3-mediated potentiation of ISG expression was associated with robust cell-intrinsic restriction of LGTV replication in cerebellar granule cell neurons. These findings further illuminate the complex roles of RIPK3 signaling in the coordination of neuroimmune responses to viral infection, as well as provide new insight into the mechanisms of region-specific innate immune signaling in the CNS.

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Section: Methodsmentioning

confidence: 99%

RIPK3 promotes brain region-specific interferon signaling and restriction of tick-borne flavivirus infection

Lindman

Angel

Estevez

et al. 2023

Preprint

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“…A role for Zika virus-induced TNFa-signaling in the induction of psychiatric disorders has been recently reported [47]. In this case, authors suggested that ZIKVinfected neurons would be the main source of TNFa expression.…”

Section: Discussionmentioning

confidence: 82%

Zika virus infection of mature neurons from immunocompetent mice generates a disease-associated microglia and a tauopathy-like phenotype in link with a delayed interferon beta response

Manet

Mansuroglu

Conquet

et al. 2022

J Neuroinflammation

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Background Zika virus (ZIKV) infection at postnatal or adult age can lead to neurological disorders associated with cognitive defects. Yet, how mature neurons respond to ZIKV remains substantially unexplored. Methods The impact of ZIKV infection on mature neurons and microglia was analyzed at the molecular and cellular levels, in vitro using immunocompetent primary cultured neurons and microglia, and in vivo in the brain of adult immunocompetent mice following intracranial ZIKV inoculation. We have used C57BL/6 and the genetically diverse Collaborative Cross mouse strains, displaying a broad range of susceptibility to ZIKV infection, to question the correlation between the effects induced by ZIKV infection on neurons and microglia and the in vivo susceptibility to ZIKV. Results As a result of a delayed induction of interferon beta (IFNB) expression and response, infected neurons displayed an inability to stop ZIKV replication, a trait that was further increased in neurons from susceptible mice. Alongside with an enhanced expression of ZIKV RNA, we observed in vivo, in the brain of susceptible mice, an increased level of active Iba1-expressing microglial cells occasionally engulfing neurons and displaying a gene expression profile close to the molecular signature of disease-associated microglia (DAM). In vivo as well as in vitro, only neurons and not microglial cells were identified as infected, raising the question of the mechanisms underlying microglia activation following brain ZIKV infection. Treatment of primary cultured microglia with conditioned media from ZIKV-infected neurons demonstrated that type-I interferons (IFNs-I) secreted by neurons late after infection activate non-infected microglial cells. In addition, ZIKV infection induced pathological phosphorylation of Tau (pTau) protein, a hallmark of neurodegenerative tauopathies, in vitro and in vivo with clusters of neurons displaying pTau surrounded by active microglial cells. Conclusions We show that ZIKV-infected mature neurons display an inability to stop viral replication in link with a delayed IFNB expression and response, while signaling microglia for activation through IFNs-I secreted at late times post-infection. In the brain of ZIKV-infected susceptible mice, uninfected microglial cells adopt an active morphology and a DAM expression profile, surrounding and sometimes engulfing neurons while ZIKV-infected neurons accumulate pTau, overall reflecting a tauopathy-like phenotype.

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Zika virus-induced TNF-α signaling dysregulates expression of neurologic genes associated with psychiatric disorders

Cited by 2 publications

References 119 publications

RIPK3 promotes brain region-specific interferon signaling and restriction of tick-borne flavivirus infection

RIPK3 promotes brain region-specific interferon signaling and restriction of tick-borne flavivirus infection

Zika virus infection of mature neurons from immunocompetent mice generates a disease-associated microglia and a tauopathy-like phenotype in link with a delayed interferon beta response

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