Zika Virus Infects Human Fetal Brain Microglia and Induces Inflammation

Lum, Fok‐Moon; Low, Donovan; Fan, Yiping; Tan, Jeslin J. L.; Lee, Bernett; Chan, Jerry Ky; Rénia, Laurent; Ginhoux, Florent; Ng, Lisa F. P.

doi:10.1093/cid/ciw878

Cited by 144 publications

(126 citation statements)

References 27 publications

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“…All cells of the CNS are susceptible to a degree. Recent studies on ZIKV tropism in human brain cell cultures suggest similar tropism (astrocytes, oligodendrocyte precursor cells, microglia and to a lesser extent neurones) [46, 70], demonstrating the relevance of our model. The protein AXL mediates entry into human microglia and astrocytes and modulates innate immune responses [50], confirming previous studies suggesting this host factor is important for ZIKV infection [45, 63].…”

Section: Discussionmentioning

confidence: 52%

“…Many studies on the pathogenesis of ZIKV have focussed on the proliferation, survival and differentiation of CNS neural precursors; the use of iPS derived human cells conferring species-specific relevance, in some studies [4, 15, 27, 28, 41, 46, 49, 64, 68, 70, 91, 99]. However, it is not currently possible, using human cells, to generate in vitro models of the relatively more mature nervous systems, comprising differentiated neurones and glia and myelinated nerve fibres.…”

Section: Discussionmentioning

confidence: 99%

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Zika virus tropism and interactions in myelinating neural cell cultures: CNS cells and myelin are preferentially affected

Cumberworth¹,

Barrie²,

Cunningham³

et al. 2017

acta neuropathol commun

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The recent global outbreak of Zika virus (ZIKV) infection has been linked to severe neurological disorders affecting the peripheral and central nervous systems (PNS and CNS, respectively). The pathobiology underlying these diverse clinical phenotypes are the subject of intense research; however, even the principal neural cell types vulnerable to productive Zika infection remain poorly characterised. Here we used CNS and PNS myelinating cultures from wild type and Ifnar1 knockout mice to examine neuronal and glial tropism and short-term consequences of direct infection with a Brazilian variant of ZIKV. Cell cultures were infected pre- or post-myelination for various intervals, then stained with cell-type and ZIKV-specific antibodies. In bypassing systemic immunity using ex vivo culture, and the type I interferon response in Ifnar1 deficient cells, we were able to evaluate the intrinsic infectivity of neural cells. Through systematic quantification of ZIKV infected cells in myelinating cultures, we found that ZIKV infection is enhanced in the absence of the type I interferon responses and that CNS cells are considerably more susceptible to infection than PNS cells. In particular, we demonstrate that CNS axons and myelinating oligodendrocytes are especially vulnerable to injury. These results have implications for understanding the pathobiology of neurological symptoms associated with ZIKV infection. Furthermore, we provide a quantifiable ex vivo infection model that can be used for fundamental and therapeutic studies on viral neuroinvasion and its consequences.Electronic supplementary materialThe online version of this article (doi:10.1186/s40478-017-0450-8) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 52%

Section: Discussionmentioning

confidence: 99%

Zika virus tropism and interactions in myelinating neural cell cultures: CNS cells and myelin are preferentially affected

Cumberworth¹,

Barrie²,

Cunningham³

et al. 2017

acta neuropathol commun

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“…ZIKV, normally causes limited infections with symptoms such as fever, headaches, and conjunctivitis (Lum et al, 2017). However, ZIKV is also associated with brain microcephaly and ocular defects in infants, which occur during the course of pregnancy (Roach and Alcendor, 2017).…”

Section: The Relationship Between Viral Infections and Neuroinflammatmentioning

confidence: 99%

“…Following recognition by TLR-3, infection of fetal brain cells with ZIKV impairs the neurosphere and brain organoid growth. ZIKV infection has been also found in Microglia and was shown to increase the level of cytokines such as IL-6, TNF-α, and IL-1β (Lum et al, 2017). Same as WNV and ZIKV, Dengue is also a mosquito-borne RNA flavivirus.…”

Section: The Relationship Between Viral Infections and Neuroinflammatmentioning

confidence: 99%

Neuroinflammation and Infection: Molecular Mechanisms Associated with Dysfunction of Neurovascular Unit

Tohidpour

Моргун

Boitsova

et al. 2017

Front. Cell. Infect. Microbiol.

128

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Neuroinflammation is a complex inflammatory process in the central nervous system, which is sought to play an important defensive role against various pathogens, toxins or factors that induce neurodegeneration. The onset of neurodegenerative diseases and various microbial infections are counted as stimuli that can challenge the host immune system and trigger the development of neuroinflammation. The homeostatic nature of neuroinflammation is essential to maintain the neuroplasticity. Neuroinflammation is regulated by the activity of neuronal, glial, and endothelial cells within the neurovascular unit, which serves as a “platform” for the coordinated action of pro- and anti-inflammatory mechanisms. Production of inflammatory mediators (cytokines, chemokines, reactive oxygen species) by brain resident cells or cells migrating from the peripheral blood, results in the impairment of blood-brain barrier integrity, thereby further affecting the course of local inflammation. In this review, we analyzed the most recent data on the central nervous system inflammation and focused on major mechanisms of neurovascular unit dysfunction caused by neuroinflammation and infections.

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“…The activation of p53 was not restricted to NPC expressing high levels of viral antigens (Ghouzzi et al, 2016), suggesting that this might be an early event or an indirect effect of ZIKV infection in neighboring cells. Other cell types, such as microglia, astrocytes, and endothelial cells, can also be infected Lum et al, 2017;Meertens et al, 2017), but it is unknown how the interplay among different cell types contribute to the outcome of microcephaly.…”

Section: Are There Any Differences In the Neurovirulence Of Differentmentioning

confidence: 99%

Zika Virus: What Have We Learnt Since the Start of the Recent Epidemic?

2018

Frontiers Research Topics

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Zika is a viral disease transmitted mainly by mosquitoes of the genus Aedes. In recent years, it has expanded geographically, changing from an endemic mosquito-borne disease across equatorial Asia and Africa, to an epidemic disease causing large outbreaks in several areas of the world. With the recent Zika virus (ZIKV) outbreaks in the Americas, the disease has become a focus of attention of public health agencies and of the international research community, especially due to an association with neurological disorders in adults and to the severe neurological and ophthalmological abnormalities found in fetuses and newborns of mothers exposed to ZIKV during pregnancy. A large number of studies have been published in the last 3 years, revealing the structure of the virus, how it is transmitted and how it affects human cells. Many different animal models have been developed, which recapitulate several features of ZIKV disease and its neurological consequences. Moreover, several vaccine candidates are now in active preclinical development, and three of them have already entered phase I clinical trials. Likewise, many different compounds targeting viral and cellular components are being tested in in vitro and in experimental animal models. This review aims to discuss the current state of this rapidly growing literature from a multidisciplinary perspective, as well as to present an overview of the public health response to Zika and of the perspectives for the prevention and treatment of this disease.

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Zika Virus Infects Human Fetal Brain Microglia and Induces Inflammation

Abstract: Our results highlight an important role for microglia and neuroinflammation during congenital ZIKV pathogenesis.

Cited by 144 publications

References 27 publications

Zika virus tropism and interactions in myelinating neural cell cultures: CNS cells and myelin are preferentially affected

Zika virus tropism and interactions in myelinating neural cell cultures: CNS cells and myelin are preferentially affected

Neuroinflammation and Infection: Molecular Mechanisms Associated with Dysfunction of Neurovascular Unit

Zika Virus: What Have We Learnt Since the Start of the Recent Epidemic?

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