Modeling neuro-immune interactions during Zika virus infection

Mesci, Pinar; Macia, Ángela; LaRock, Christopher N.; Tejwani, Leon; Fernandes, Isabella Rodrigues; Suarez, Nicole A.; Zanotto, Paolo Marinho de Andrade; Beltrão-Braga, Patrícia Cristina Baleeiro; Nizet, Victor; Muotri, Alysson R.

doi:10.1093/hmg/ddx382

Cited by 52 publications

(41 citation statements)

References 62 publications

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“…We note that pMGLs, in contrast to NPCs, can still mount a response to the virus: in certain circumstances they may help limit viral spread in the CNS parenchyma, for example, at later stages when more mature and present at higher density. A study published while this manuscript was under review (43), supporting many of our own findings, suggest this may indeed be the case: cocultures of NPCs and iPS-derived macrophages demonstrated less viral positivity than NPCs alone after exposure to ZIKV. The authors concluded there was active removal of infected NPCs by macrophages, highlighting the complex interplay between their role as vectors and as protective actors.…”

Section: Discussionsupporting

confidence: 78%

Human induced pluripotent stem cell-derived glial cells and neural progenitors display divergent responses to Zika and dengue infections

Muffat

Omer

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

114

111

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Maternal Zika virus (ZIKV) infection during pregnancy is recognized as the cause of an epidemic of microcephaly and other neurological anomalies in human fetuses. It remains unclear how ZIKV accesses the highly vulnerable population of neural progenitors of the fetal central nervous system (CNS), and which cell types of the CNS may be viral reservoirs. In contrast, the related dengue virus (DENV) does not elicit teratogenicity. To model viral interaction with cells of the fetal CNS in vitro, we investigated the tropism of ZIKV and DENV for different induced pluripotent stem cell-derived human cells, with a particular focus on microglia-like cells. We show that ZIKV infected isogenic neural progenitors, astrocytes, and microglia-like cells (pMGLs), but was only cytotoxic to neural progenitors. Infected glial cells propagated ZIKV and maintained ZIKV load over time, leading to viral spread to susceptible cells. DENV triggered stronger immune responses and could be cleared by neural and glial cells more efficiently. pMGLs, when cocultured with neural spheroids, invaded the tissue and, when infected with ZIKV, initiated neural infection. Since microglia derive from primitive macrophages originating in proximity to the maternal vasculature, they may act as a viral reservoir for ZIKV and establish infection of the fetal brain. Infection of immature neural stem cells by invading microglia may occur in the early stages of pregnancy, before angiogenesis in the brain rudiments. Our data are also consistent with ZIKV and DENV affecting the integrity of the blood-brain barrier, thus allowing infection of the brain later in life.

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Section: Discussionsupporting

confidence: 78%

Human induced pluripotent stem cell-derived glial cells and neural progenitors display divergent responses to Zika and dengue infections

Muffat

Omer

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

114

111

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“…42 Further, microglia have been found to devour ZIKV-infected NPCs and to transmit the virus to uninfected NPCs. 43 This is consistent with the previously mentioned Trojan horse mechanism.…”

Section: Glial Cellssupporting

confidence: 91%

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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“…During human fetal brain development, as neurons and glia emerge from NPs, or as microglia migrate into the brain, these cell types are susceptible to ZIKV infection. Evidence suggests that neuronal function can be impaired by ZIKV (40), and glial cells that are less acutely impacted could serve as viral reservoirs (8,41). In the current study, we investigated whether ZIKV host factors in NPs also mediate infection of astrocytes.…”

Section: Discussionmentioning

confidence: 97%

Genome-wide CRISPR screen for Zika virus resistance in human neural cells

Muffat

Javed

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

103

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Zika virus (ZIKV) is a neurotropic and neurovirulent arbovirus that has severe detrimental impact on the developing human fetal brain. To date, little is known about the factors required for ZIKV infection of human neural cells. We identified ZIKV host genes in human pluripotent stem cell (hPSC)-derived neural progenitors (NPs) using a genome-wide CRISPR-Cas9 knockout screen. Mutations of host factors involved in heparan sulfation, endocytosis, endoplasmic reticulum processing, Golgi function, and interferon activity conferred resistance to infection with the Uganda strain of ZIKV and a more recent North American isolate. Host genes essential for ZIKV replication identified in human NPs also provided a low level of protection against ZIKV in isogenic human astrocytes. Our findings provide insights into host-dependent mechanisms for ZIKV infection in the highly vulnerable human NP cells and identify molecular targets for potential therapeutic intervention.

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Modeling neuro-immune interactions during Zika virus infection

Cited by 52 publications

References 62 publications

Human induced pluripotent stem cell-derived glial cells and neural progenitors display divergent responses to Zika and dengue infections

Human induced pluripotent stem cell-derived glial cells and neural progenitors display divergent responses to Zika and dengue infections

Research advancements in the neurological presentation of flaviviruses

Genome-wide CRISPR screen for Zika virus resistance in human neural cells

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