Zika Virus Targets Glioblastoma Stem Cells through a SOX2-Integrin αvβ5 Axis

Zhu, Zhe; Mesci, Pinar; Bernatchez, Jean; Gimple, Ryan C.; Wang, Xiuxing; Schäfer, Simon; Wettersten, Hiromi I.; Beck, Sungjun; Clark, Alex E.; Wu, Qiulian; Prager, Briana C.; Kim, Leo J.Y.; Dhanwani, Rekha; Sharma, Sonia; Garancher, Alexandra; Weis, Sara M.; Mack, Stephen C.; Negraes, Priscilla D.; Trujillo, Cleber A.; Penalva, Luiz O. F.; Feng, Jing; Lan, Zhou; Zhang, Rong; Wessel, Alex W.; Dhawan, Sanjay; Diamond, Michael S.; Chen, Clark C.; Wechsler‐Reya, Robert J.; Gage, Fred H.; Hu, Hongzhen; Siqueira-Neto, Jair L.; Muotri, Alysson R.; Cheresh, David A.; Rich, Jeremy

doi:10.1016/j.stem.2019.11.016

Cited by 134 publications

(94 citation statements)

References 103 publications

(102 reference statements)

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“…As a follow-up of these observations, a strong inflammatory response, as revealed by induction of IFNs, was identified in RPE after ZIKV infection [110]. The relevance of inflammation as an effective host countermeasure against ZIKV infection is emphasized by the sex determining region Y (SRY)-box 2 (SOX2)-dependent susceptibility of glioblastoma stem cells, as SOX2 expression was associated with a reduced innate antiviral response [111].…”

Section: The Infection Of Pluripotent Stem Cell-based Models Of Humanmentioning

confidence: 89%

Pluripotent Stem Cell-Based Models: A Peephole into Virus Infections during Early Pregnancy

Claus

Jung

Hübschen

2020

Cells

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The rubella virus (RV) was the first virus shown to be teratogenic in humans. The wealth of data on the clinical symptoms associated with congenital rubella syndrome is in stark contrast to an incomplete understanding of the forces leading to the teratogenic alterations in humans. This applies not only to RV, but also to congenital viral infections in general and includes (1) the mode of vertical transmission, even at early gestation, (2) the possible involvement of inflammation as a consequence of an activated innate immune response, and (3) the underlying molecular and cellular alterations. With the progress made in the development of pluripotent stem cell-based models including organoids and embryoids, it is now possible to assess congenital virus infections on a mechanistic level. Moreover, antiviral treatment options can be validated, and newly emerging viruses with a potential impact on human embryonal development, such as that recently reflected by the Zika virus (ZIKV), can be characterized. Here, we discuss human cytomegalovirus (HCMV) and ZIKV in comparison to RV as viruses with well-known congenital pathologies and highlight their analysis on current models for the early phase of human development. This includes the implications of their genetic variability and, as such, virus strain-specific properties for their use as archetype models for congenital virus infections. In this review, we will discuss the use of induced pluripotent stem cells (iPSC) and derived organoid systems for the study of congenital virus infections with a focus on their prominent aetiologies, HCMV, ZIKV, and RV. Their assessment on these models will provide valuable information on how human development is impaired by virus infections; it will also add new insights into the normal progression of human development through the analysis of developmental pathways in the context of virus-induced alterations. These are exciting perspectives for both developmental biology and congenital virology.

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Section: The Infection Of Pluripotent Stem Cell-based Models Of Humanmentioning

confidence: 89%

Pluripotent Stem Cell-Based Models: A Peephole into Virus Infections during Early Pregnancy

Claus

Jung

Hübschen

2020

Cells

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“…With the emergence of the new neurotropic ZIKV with its unexpected preference for infecting GSCs, a new research area for glioma virotherapy opened up [26,[28][29][30]43,44]. In regard to Flaviviridae, recombinant reporter viruses, for example, for West Nile and Dengue virus, were constructed using the original flavivirus genome as a packaging template [45,46].…”

Section: Discussionmentioning

confidence: 99%

“…In these studies, a selective killing on GSCs within the tumor was observed [26]. Recent findings demonstrate that the entry of ZIKV into GSCs is supported by Integrin α v β 5 because viral entry can be specifically blocked by an α v β 5 -specific antibody or by the cyclic peptide Cilengitide (cyclo-RGDfV-) [27], a peptide that is highly specific for binding to α v integrin [28][29][30]. Integrin α v as part of the integrins α v β 3 and α v β 5 have been shown to play a role in a variety of tumors, particularly malignant gliomas.…”

mentioning

confidence: 96%

Zikavirus prME Envelope Pseudotyped Human Immunodeficiency Virus Type-1 as a Novel Tool for Glioblastoma-Directed Virotherapy

Kretschmer

Kadlubowska

Hoffmann

et al. 2020

Cancers

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Glioblastoma multiforme is the most lethal type of brain tumor that is not yet curable owing to its frequent resurgence after surgery. Resistance is mainly caused by the presence of a subpopulation of tumor cells, the glioma stem cells (GSCs), which are highly resistant to radiation and chemotherapy. In 2015, Zikavirus (ZIKV)-induced microcephaly emerged in newborns, indicating that ZIKV has a specific neurotropism. Accordingly, an oncolytic tropism for infecting GSCs was demonstrated in a murine tumor model. Like other flaviviruses, ZIKV is enveloped by two proteins, prM and E. The pME expression plasmid along with the HIV-1 vector pNL Luc AM generated prME pseudotyped viral particles. Four different prME envelopes, Z1 to Z4, were cloned, and the corresponding pseudotypes, Z1-to Z4-HIVluc, produced by this two-plasmid system, were tested for entry efficiency using Vero-B4 cells. The most efficient pseudotype, Z1-HIVluc, also infected glioma-derived cell lines U87 and 86HG39. The pseudotype system was then extended by using a three-plasmid system including pME-Z1, the HIV-1 packaging plasmid psPAX2, and the lentiviral vector pLenti-luciferase-P2A-Neo. The corresponding pseudotype, designated Z1-LENTIluc, also infected U87 and 86HG39 cells. Altogether, a pseudotyped virus especially targeting glioma-derived cells might be a promising candidate for a prospective glioblastoma-directed virotherapy. Cancers 2020, 12, 1000 2 of 18 biology, leading to the generation of recombinant, genetically modified virus candidates. Clinical trials have been completed using modified versions of herpes simplex virus [7-12], adenovirus [13,14], Newcastle disease virus [15], reovirus [16,17], parvovirus [18], and poliovirus [19]. Some of these studies demonstrated that a small subset of patients had a benefit from such virotherapy applications, but the statistical significance of these findings must be demonstrated in larger control trials [20].A new discovery, with a high impact on the future aspects of glioma virotherapy, was that Zikavirus (ZIKV) showed a specific neurotropism for glial cells [21]. ZIKV is a new emerging mosquito-borne virus belonging to the Flaviviridae family [22]. In the Flaviviridae family, all members are enveloped viruses with two external, membranous proteins, the envelope E and the precursor of the membrane protein prM [23], both relevant for viral entry. In early 2015, abnormal rates of ZIKV infections were seen in Brazil, and in late 2015, an unexpected high number of newborns showed microcephaly, a disease where a baby's head is much smaller than expected. Altogether, the new emerging ZIKV was shown to be the cause of Guillain-Barré syndrome (GBS), microcephaly, and other congenital brain abnormalities, proving its neurotropic phenotype [24]. An interesting finding was the oncolytic activity of ZIKV against GSCs [25]. A selective effect of ZIKV was observed for GSCs, causing loss of self-renewal and proliferation in glioblastoma organoids. In mice, ZIKV infection prolonged survival by slowing down tumor g...

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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

Self Cite

572

537

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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 ...

show abstract

Zika Virus Targets Glioblastoma Stem Cells through a SOX2-Integrin αvβ5 Axis

Cited by 134 publications

References 103 publications

Pluripotent Stem Cell-Based Models: A Peephole into Virus Infections during Early Pregnancy

Pluripotent Stem Cell-Based Models: A Peephole into Virus Infections during Early Pregnancy

Zikavirus prME Envelope Pseudotyped Human Immunodeficiency Virus Type-1 as a Novel Tool for Glioblastoma-Directed Virotherapy

The continued threat of emerging flaviviruses

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