Zika virus E protein dysregulate mir-204/WNT2 signalling in human fetal neural stem cells

Bhagat, Reshma; Rajpara, Prateek; Kaur, Guneet; Gupta, Karnika; Seth, Pankaj

doi:10.1016/j.brainresbull.2021.08.009

Cited by 10 publications

(9 citation statements)

References 41 publications

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“…As the membrane fusion and subsequent entry of the virus is facilitated by E protein, it proves to be a conducive target for drug therapy and vaccine development 52,53 . Our previous lab studies have focused on how ZIKV E protein perturbed the miRNA circuitry of human fetal neural stem cells (fNSCs) pertaining to cell cycle arrest and inhibition of proliferation 19,20 . This strongly highlights the fact that E protein plays eminent role in pathogenicity of the virus.…”

Section: Discussionmentioning

confidence: 99%

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Zika virus E protein alters blood-brain barrier by modulating brain microvascular endothelial cell and astrocyte functions

Kaur¹,

Pant²,

Bhagat³

et al. 2023

Preprint

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Neurotropic viruses can cross the otherwise dynamically regulated blood-brain barrier (BBB) and affect the brain cells. Zika virus (ZIKV) is an enveloped neurotropic Flavivirus known to cause severe neurological complications, such as encephalitis and foetal microcephaly. In the present study, we used human brain microvascular endothelial cells (hBMECs) and human progenitor derived astrocytes to form a physiologically relevant BBB model. We used this model to investigate the effects of ZIKV envelope (E) protein on properties of cells comprising the BBB. E protein is the principal viral protein involved in interaction with host cell surface receptors, facilitating the viral entry. Our findings show that ZIKV E protein results in activation of both hBMECs and astrocytes. hBMECs showed reduced expression of endothelial junction proteins - ZO-1, Occludin and VE-Cadherin, which are crucial in establishing and maintaining the BBB. As a result, ZIKV E protein triggered alteration in BBB integrity and permeability. We also found upregulation of genes involved in leukocyte recruitment along with increased proinflammatory chemokines and cytokines upon exposure to E protein. Furthermore, E protein resulted in astrogliosis as seen by increased expression of GFAP and Vimentin. Both BBB cell types exhibited inflammatory response following exposure to E protein which may influence viral access into the central nervous system (CNS), resulting in infection of other CNS cells. Overall, our study provides valuable insights into the transient changes that occur at the site of BBB upon ZIKV infection.

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Section: Discussionmentioning

confidence: 99%

“…Full length ZIKV E protein cloned in pCAGIG-IRES-GFP expression vector was a kind gift from Dr Shyamala Mani (IISc, Bangalore, India) also used in previous studies 19,20 . Cells (80% confluent) were transfected using lipofectamine 3000 (Invitrogen, San Diego, CA, USA, Cat# L3000008) according to the manufacturer’s protocol.…”

Section: Methodsmentioning

confidence: 99%

Zika virus E protein alters blood-brain barrier by modulating brain microvascular endothelial cell and astrocyte functions

Kaur¹,

Pant²,

Bhagat³

et al. 2023

Preprint

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“…In this view, we collected the differentially expressed miRNAs infected by Flavivirus genus members, mainly DENV, JEV, WNV, and ZIKV. Through the classification of regulatory effects, it is found that these miRNAs principally participate in the process of viral replication, neuroinflammation, neurogenesis and so on ( Escalera-Cueto et al, 2015 ; Liu et al, 2016 ; Castrillón-Betancur and Urcuqui-Inchima, 2017 ; Dang et al, 2019 ; Hazra et al, 2019 ; Mukherjee et al, 2019 ; Bhagat et al, 2021 ). Furthermore, several miRNAs show identical or opposite expression by different flavivirus infection and thus play similar or opposite roles.…”

Section: Discussionmentioning

confidence: 99%

Regulatory Role of Host MicroRNAs in Flaviviruses Infection

et al. 2022

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MicroRNAs (miRNAs) are small non-coding RNA that affect mRNA abundance or translation efficiency by binding to the 3′UTR of the mRNA of the target gene, thereby participating in multiple biological processes, including viral infection. Flavivirus genus consists of small, positive-stranded, single-stranded RNA viruses transmitted by arthropods, especially mosquitoes and ticks. The genus contains several globally significant human/animal pathogens, such as Dengue virus, Japanese encephalitis virus, West Nile virus, Zika virus, Yellow fever virus, Tick-borne encephalitis virus, and Tembusu virus. After flavivirus invades, the expression of host miRNA changes, exerting the immune escape mechanism to create an environment conducive to its survival, and the altered miRNA in turn affects the life cycle of the virus. Accumulated evidence suggests that host miRNAs influence flavivirus replication and host–virus interactions through direct binding of viral genomes or through virus-mediated host transcriptome changes. Furthermore, miRNA can also interweave with other non-coding RNAs, such as long non-coding RNA and circular RNA, to form an interaction network to regulate viral replication. A variety of non-coding RNAs produced by the virus itself exert similar function by interacting with cellular RNA and viral RNA. Understanding the interaction sites between non-coding RNA, especially miRNA, and virus/host genes will help us to find targets for antiviral drugs and viral therapy.

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“…Furthermore, ZIKV E protein induces G2/M cell cycle arrest and apoptosis via an intrinsic cell death signaling pathway, which may contribute to abnormal neurogenesis 56 . Similar to capsid protein, E protein impairs the proliferation and differentiation of fNSCs by modulating microRNA circuitry, such as mir‐204 for WNT2 signaling, which is crucial for the maintenance of “stemness” in NSCs 57,58 …”

Section: Prm‐ementioning

confidence: 99%

Modulation of cellular machineries by Zika virus‐encoded proteins

Dong

Xiao

Liang

2022

Journal of Medical Virology

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The strain of Zika virus (ZIKV) that circulated during the 2015 epidemic in Brazil has been associated with more than 2000 cases of microcephaly from September 2015 through November 2016. The viral genome determines the biology and pathogenesis of a virus and the virus employs its own gene products to evade host immune surveillance, manipulate cellular machineries, and establish efficient replication. Therefore, understanding the functions of virus‐encoded protein not only aids the knowledge of ZIKV biology but also guides the development of anti‐ZIKV drugs. In this review, we focus on 10 proteins encoded by ZIKV and summarize their functions in ZIKV replication and pathogenesis according to studies published in the past 6 years.

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Zika virus E protein dysregulate mir-204/WNT2 signalling in human fetal neural stem cells

Cited by 10 publications

References 41 publications

Zika virus E protein alters blood-brain barrier by modulating brain microvascular endothelial cell and astrocyte functions

Zika virus E protein alters blood-brain barrier by modulating brain microvascular endothelial cell and astrocyte functions

Regulatory Role of Host MicroRNAs in Flaviviruses Infection

Modulation of cellular machineries by Zika virus‐encoded proteins

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