Integrin αvβ5 Internalizes Zika Virus during Neural Stem Cells Infection and Provides a Promising Target for Antiviral Therapy

Wang, Shaobo; Zhang, Qiong; Tiwari, Shashi Kant; Lichinchi, Gianluigi; Yau, Edwin; Hui, Hui; Li, Wanyu; Furnari, Frank B.; Rana, Tariq M.

doi:10.1016/j.celrep.2019.11.020

Cited by 69 publications

(60 citation statements)

References 79 publications

(127 reference statements)

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“…As highly conserved molecules expressed by almost every cell type, integrins serve as entry receptors of several viruses, including Adenovirus [52], Foot-and-mouth disease virus [53], hantavirus [54], human coxsackievirus A9 [55], human echovirus 9 [56], and WNV [57]. A very recent study by Wang et al identified integrin avb5 as an entry receptor for ZIKV to establish an infection in neural stem cells [58]. Similarly, our data from ZIKV entry assay confirm that ITGAV is essential for the initiation of ZIKV internalization.…”

Section: Discussionmentioning

confidence: 99%

mRNA and miRNA profiling of Zika virus-infected human umbilical cord mesenchymal stem cells identifies miR-142-5p as an antiviral factor

Seong

Lee

Cho

et al. 2020

Emerging Microbes & Infections

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Zika virus (ZIKV) infection during pregnancy is associated with congenital brain abnormalities, a finding that highlights the urgent need to understand mother-to-fetus transmission mechanisms. Human umbilical cord mesenchymal stem cells (hUCMSCs) are susceptible to ZIKV infection but the underlying mechanisms of viral susceptibility remain largely unexplored. In this study, we have characterized and compared host mRNA and miRNA expression profiles in hUCMSCs after infection with two lineages of ZIKV, African (MR766) and Asian (PRVABC59). RNA sequencing analysis identified differentially expressed genes involved in anti-viral immunity and mitochondrial dynamics following ZIKV infection. In particular, ZIKV-infected hUCMSCs displayed mitochondrial elongation and the treatment of hUCMSCs with mitochondrial fission inhibitor led to a dose-dependent increase in ZIKV gene expression and decrease in antiviral signalling pathways. Moreover, small RNA sequencing analysis identified several significantly up-or downregulated microRNAs. Interestingly, miR-142-5p was significantly downregulated upon ZIKV infection, whereas cellular targets of miR-142-5p, IL6ST and ITGAV, were upregulated. Overexpression of miR-142-5p resulted in the suppression of ZIKV replication. Furthermore, blocking ITGAV expression resulted in a significant suppression of ZIKV binding to cells, suggesting a potential role of ITGAV in ZIKV entry. In conclusion, these results demonstrate both common and specific host responses to African and Asian ZIKV lineages and indicate miR-142-5p as a key regulator of ZIKV replication in the umbilical cords.

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Section: Discussionmentioning

confidence: 99%

mRNA and miRNA profiling of Zika virus-infected human umbilical cord mesenchymal stem cells identifies miR-142-5p as an antiviral factor

Seong

Lee

Cho

et al. 2020

Emerging Microbes & Infections

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“…Relationships between host attachment factor expression and viral tropism in vivo have not been established. Some flavivirus attachment factors (for example, TAM and integrin receptors) capable of binding virions also transduce signals into target cells, which has the potential to augment infection and further complicates the role and definition of host attachment molecules [39][40][41][42] .…”

Section: E-diismentioning

confidence: 99%

The continued threat of emerging flaviviruses

Pierson

Diamond²

2020

Nat Microbiol

661

627

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F laviviruses are single-stranded RNA viruses vectored principally by arthropods that cause severe illnesses in humans. The extensive global spread and epidemic transmission of flaviviruses during the last seven decades has been remarkable. The mosquito-borne dengue viruses (DENV) infect an estimated 400 million humans each year; more than a quarter of the world's population lives in areas where DENV is now endemic 1 . By comparison, only sporadic DENV epidemics were documented before the Second World War 2 . The introductions of West Nile (WNV) and Zika (ZIKV) viruses into the Western Hemisphere was followed by rapid geographical spread, large numbers of human infections and considerable morbidity 3,4 . Ongoing yellow fever virus (YFV) transmission and its encroachment on urban environments, despite the existence of an effective vaccine, poses a serious public health challenge 5-7 . Other flaviviruses present ongoing health risks or are beginning to emerge in different parts of the world, including Japanese encephalitis virus (JEV), tick-borne encephalitis virus (TBEV) and Usutu virus (USUV).The epidemic potential of flaviviruses reflects many factors related to the unique characteristics of their insect vectors, the consequences of poorly planned urbanization that creates ideal arthropod breeding habitats, the geographical expansion of vectors, changing environmental conditions and extensive global travel 8,9 . Beyond arthropods and humans, flaviviruses are also known to infect a wide array of animal species and can be important veterinary pathogens that threaten economically important domesticated animals 10-14 . These vertebrate animal hosts may constitute important stable reservoirs and contribute to defining conditions that support the introduction of new viral species and transmission among humans 15 . The continued threat of flavivirus emergence and re-emergence highlights a need for a detailed fundamental understanding of the biology of these viruses, the immune responses that can contain them and the possible countermeasures that can blunt their impact on public health should new outbreaks occur. Flavivirus structure and replicationFlaviviruses are small (~50 nm) spherical virus particles that incorporate a single genomic RNA of positive-sense polarity encoding three structural and seven non-structural proteins (Fig. 1a). Our knowledge of the biology of flaviviruses has advanced considerably with the availability of high-resolution structures of viral structural proteins and of virions at different stages of the replication cycle or in complex with antibodies or host factors 16 . Crystal structures of the enzymatic non-structural proteins also have been solved, accelerating advances in an understanding of virus replication and pathogenesis [17][18][19] and enabling structure-guided drug discovery, as reviewed elsewhere 20 .Virion structure and morphogenesis. Flaviviruses are assembled using three viral structural proteins (C, prM and E), a host lipid envelope and the viral genomic RNA. The structure of ...

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“…ZIKV preferentially infects neuronal progenitor cells (NPCs) in the developing foetal brain and has also been found in tissues outside the central nervous system (CNS), including the eyes, testis, and female reproductive tract organs [16][17][18][19]. However, few reports focus on the basis of ZIKV cellular and tissue tropism [20][21][22]. ZIKV infection induces a series of host cell innate immune responses, pro-inflammatory responses, and humoral immune responses by producing protective and neutralizing antibodies in humans [17,23,24].…”

Section: Introductionmentioning

confidence: 99%

The activation of antiviral RNA interference not only exists in neural progenitor cells but also in somatic cells in mammals

Zhang

Liu

et al. 2020

Emerging Microbes & Infections

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The RNA interference (RNAi) pathway directs an important antiviral immunity mechanism in plants and invertebrates. Recently, we and others have demonstrated that the antiviral RNAi response is also conserved in mammals, at least to five distinct RNA viruses, including Zika virus (ZIKV). ZIKV may preferentially infect neuronal progenitor cells (NPCs) in the developing foetal brain. Ex vivo ZIKV infection induces RNAi-mediated antiviral response in human NPCs, but not in the more differentiated NPCs or somatic cells. However, litter is known about the in vivo property or function of the virus-derived small-interfering RNAs (vsiRNAs) targeting ZIKV. Here we report a surprising observation: different from ex vivo observations, viral small RNAs (vsRNAs) targeting ZIKV were produced in vivo upon infection in both central neuron system (CNS) and muscle tissues. In addition, our findings demonstrate the production of canonical vsiRNAs in murine CNS upon antiviral RNAi activation by Sindbis virus (SINV), suggesting the possibility of antiviral immune strategy applied by mammals in the CNS.

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Integrin αvβ5 Internalizes Zika Virus during Neural Stem Cells Infection and Provides a Promising Target for Antiviral Therapy

Cited by 69 publications

References 79 publications

mRNA and miRNA profiling of Zika virus-infected human umbilical cord mesenchymal stem cells identifies miR-142-5p as an antiviral factor

mRNA and miRNA profiling of Zika virus-infected human umbilical cord mesenchymal stem cells identifies miR-142-5p as an antiviral factor

The continued threat of emerging flaviviruses

The activation of antiviral RNA interference not only exists in neural progenitor cells but also in somatic cells in mammals

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