Inhibition of innate immune response ameliorates Zika virus-induced neurogenesis deficit in human neural stem cells

Xu, Pei; Gao, Junling; Shan, Chao; Dunn, Tiffany J.; Xie, Xuping; Xia, Hongjie; Zou, Jing; Thames, Beatriz H; Sajja, Amulya; Yu, Yongjia; Freiberg, Alexander N.; Vasilakis, Nikos; Shi, Pei–Yong; Weaver, Scott C.; Wu, Ping

doi:10.1371/journal.pntd.0009183

Cited by 6 publications

(6 citation statements)

References 53 publications

(54 reference statements)

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“…Our findings are in contrast to studies where NSCs are directly infected and killed by the virus, as has been seen for murine cytomegalovirus and ZIKV (He et al, 2020; Mutnal et al, 2011; Tiwari et al, 2020). However, an in vitro study on human neural stem progenitor cells (hNSCs) similarly showed that the stage of differentiation affected responses to ZIKV viruses, where neurogenesis was inhibited in NSCs in early stages of differentiation more severely than those in late differentiation (Xu et al, 2021). The present study supports our idea that the NSC pool is not monolithic and that the stage of NSC differentiation influences the sensitivity and response to the inflammatory microenvironment during infection.…”

Section: Discussionmentioning

confidence: 99%

Perturbations in neural stem cell function during a neurotropic viral infection in juvenile mice

Kamte,

Chandwani,

London

et al. 2023

Journal of Neurochemistry

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Viral infections of the central nervous system (CNS) often cause worse neurological outcomes in younger hosts. Throughout childhood, the brain undergoes extensive development and refinement to produce functional neural networks. Network function is maintained partly with the help of neural stem cells (NSCs) that replace neuronal and glia subtypes in the two neurogenic niches of the brain (the hippocampus and subventricular zone). Accumulating evidence suggests that viruses disrupt NSC function in adulthood and infancy, but the in vivo impact of childhood infections on acute and long‐term NSC function is unknown. Using a juvenile mouse model of measles virus (MeV) infection, where only mature neurons in the brain are infected, we defined the effects of the antiviral immune response on NSCs from juvenile to adult stages of life. We found that (a) virus persists in the brains of survivors despite an anti‐viral immune response; (b) NSC numbers decrease dramatically during early infection, but ultimately stabilize in adult survivors; (c) infection is associated with mild apoptosis throughout the juvenile brain, but NSC proliferation is unchanged; (d) the loss of NSC numbers is dependent upon the stage of NSC differentiation; and (e) immature neurons increase early during infection, concurrent with depletion of NSC pools. Collectively, we show that NSCs are exquisitely sensitive to the inflammatory microenvironment created during neuron‐restricted MeV infection in juveniles, responding with an early loss of NSCs but increased neurogenesis. These studies provide insight into potential cellular mechanisms associated with long‐term neurological deficits in survivors of childhood CNS infections.image

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Section: Discussionmentioning

confidence: 99%

Perturbations in neural stem cell function during a neurotropic viral infection in juvenile mice

Kamte,

Chandwani,

London

et al. 2023

Journal of Neurochemistry

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“…The activation of IFN-associated responses by ZIKV was further reported in primary cultures of human fetal NSC/NPCs [80]. Pharmacological inhibition of the overactivated innate immune responses counteracted ZIKV-induced neurogenesis deficit [80], thus indicating that coordinating the host innate immune responses in NSCs/NPCs after ZIKV infection could be a promising therapeutic approach to attenuate ZIKV-associated neuropathology.…”

Section: Zika and Nscs/npcsmentioning

confidence: 95%

Zika Virus: A New Therapeutic Candidate for Glioblastoma Treatment

Francipane

Douradinha

Chinnici

et al. 2021

IJMS

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Glioblastoma (GBM) is the most aggressive among the neurological tumors. At present, no chemotherapy or radiotherapy regimen is associated with a positive long-term outcome. In the majority of cases, the tumor recurs within 32–36 weeks of initial treatment. The recent discovery that Zika virus (ZIKV) has an oncolytic action against GBM has brought hope for the development of new therapeutic approaches. ZIKV is an arbovirus of the Flaviviridae family, and its infection during development has been associated with central nervous system (CNS) malformations, including microcephaly, through the targeting of neural stem/progenitor cells (NSCs/NPCs). This finding has led various groups to evaluate ZIKV’s effects against glioblastoma stem cells (GSCs), supposedly responsible for GBM onset, progression, and therapy resistance. While preliminary data support ZIKV tropism toward GSCs, a more accurate study of ZIKV mechanisms of action is fundamental in order to launch ZIKV-based clinical trials for GBM patients.

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“…A normal and important response to viral infection is the induction of interferon (IFN) and inflammatory pathways, with the JAK/STAT signaling pathway key to many of these immune/inflammatory responses. This pathway can be influenced by Rho GTPases, such as Rac1 in response to IFN-γ [116] and the innate TLR3-and IFN-driven responses, resulting in impaired neurogenesis [117]. Additionally, these pathways are downregulated in a temporal manner by suppressors of cytokine signaling (SOCS) 1 and 3 to resolve these early innate cytokine/antiviral responses [118,119].…”

Section: Socs1-mediated Degradation or Usp9x-mediated Activation Of Vav?mentioning

confidence: 99%

Vav Proteins in Development of the Brain: A Potential Relationship to the Pathogenesis of Congenital Zika Syndrome?

Norbury

Jolly

Kris

et al. 2022

Viruses

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Zika virus (ZIKV) infection during pregnancy can result in a significant impact on the brain and eye of the developing fetus, termed congenital zika syndrome (CZS). At a morphological level, the main serious presentations of CZS are microcephaly and retinal scarring. At a cellular level, many cell types of the brain may be involved, but primarily neuronal progenitor cells (NPC) and developing neurons. Vav proteins have guanine exchange activity in converting GDP to GTP on proteins such as Rac1, Cdc42 and RhoA to stimulate intracellular signaling pathways. These signaling pathways are known to play important roles in maintaining the polarity and self-renewal of NPC pools by coordinating the formation of adherens junctions with cytoskeletal rearrangements. In developing neurons, these same pathways are adopted to control the formation and growth of neurites and mediate axonal guidance and targeting in the brain and retina. This review describes the role of Vavs in these processes and highlights the points of potential ZIKV interaction, such as (i) the binding and entry of ZIKV in cells via TAM receptors, which may activate Vav/Rac/RhoA signaling; (ii) the functional convergence of ZIKV NS2A with Vav in modulating adherens junctions; (iii) ZIKV NS4A/4B protein effects on PI3K/AKT in a regulatory loop via PPI3 to influence Vav/Rac1 signaling in neurite outgrowth; and (iv) the induction of SOCS1 and USP9X following ZIKV infection to regulate Vav protein degradation or activation, respectively, and impact Vav/Rac/RhoA signaling in NPC and neurons. Experiments to define these interactions will further our understanding of the molecular basis of CZS and potentially other developmental disorders stemming from in utero infections. Additionally, Vav/Rac/RhoA signaling pathways may present tractable targets for therapeutic intervention or molecular rationale for disease severity in CZS.

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Inhibition of innate immune response ameliorates Zika virus-induced neurogenesis deficit in human neural stem cells

Cited by 6 publications

References 53 publications

Perturbations in neural stem cell function during a neurotropic viral infection in juvenile mice

Perturbations in neural stem cell function during a neurotropic viral infection in juvenile mice

Zika Virus: A New Therapeutic Candidate for Glioblastoma Treatment

Vav Proteins in Development of the Brain: A Potential Relationship to the Pathogenesis of Congenital Zika Syndrome?

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