Axl Mediates ZIKA Virus Entry in Human Glial Cells and Modulates Innate Immune Responses

Meertens, Laurent; Labeau, Athena; Dejarnac, Ophélie; Cipriani, Sara; Sinigaglia, Laura; Bonnet-Madin, Lucie; Charpentier, Tifenn Le; Hafirassou, Mohamed Lamine; Zamborlini, Alessia; Cao-Lormeau, Van-Mai; Coulpier, Muriel; Missé, Dorothée; Jouvenet, Nolwenn; Tabibiazar, Ray; Gressèns, Pierre; Schwartz, Olivier; Amara, Ali

doi:10.1016/j.celrep.2016.12.045

Cited by 386 publications

(459 citation statements)

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“…Evidence from clinical and animal studies indicates that ZIKV is unique among flaviviruses in that it can persist in testes (9,10) and fetal brain (11)(12)(13). Consistent with this idea, studies from our laboratory and others have revealed multiple mechanisms used by ZIKV to evade the host interferon system (14)(15)(16), an indispensable antiviral response that controls ZIKV infection and pathogenesis (17,18). How the virus counteracts other cellular antiviral pathways is largely unknown.…”

mentioning

confidence: 71%

Zika Virus Hijacks Stress Granule Proteins and Modulates the Host Stress Response

Hou

Kumar

et al. 2017

J Virol

114

132

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Zika virus (ZIKV), a member of the Flaviviridae family, has recently emerged as an important human pathogen with increasing economic and health impact worldwide. Because of its teratogenic nature and association with the serious neurological condition Guillain-Barré syndrome, a tremendous amount of effort has focused on understanding ZIKV pathogenesis. To gain further insights into ZIKV interaction with host cells, we investigated how this pathogen affects stress response pathways. While ZIKV infection induces stress signaling that leads to phosphorylation of eIF2␣ and cellular translational arrest, stress granule (SG) formation was inhibited. Further analysis revealed that the viral proteins NS3 and NS4A are linked to translational repression, whereas expression of the capsid protein, NS3/NS2B-3, and NS4A interfered with SG formation. Some, but not all, flavivirus capsid proteins also blocked SG assembly, indicating differential interactions between flaviviruses and SG biogenesis pathways. Depletion of the SG components G3BP1, TIAR, and Caprin-1, but not TIA-1, reduced ZIKV replication. Both G3BP1 and Caprin-1 formed complexes with capsid, whereas viral genomic RNA stably interacted with G3BP1 during ZIKV infection. Taken together, these results are consistent with a scenario in which ZIKV uses multiple viral components to hijack key SG proteins to benefit viral replication.IMPORTANCE There is a pressing need to understand ZIKV pathogenesis in order to advance the development of vaccines and therapeutics. The cellular stress response constitutes one of the first lines of defense against viral infection; therefore, understanding how ZIKV evades this antiviral system will provide key insights into ZIKV biology and potentially pathogenesis. Here, we show that ZIKV induces the stress response through activation of the UPR (unfolded protein response) and PKR (protein kinase R), leading to host translational arrest, a process likely mediated by the viral proteins NS3 and NS4A. Despite the activation of translational shutoff, formation of SG is strongly inhibited by the virus. Specifically, ZIKV hijacks the core SG proteins G3BP1, TIAR, and Caprin-1 to facilitate viral replication, resulting in impaired SG assembly. This process is potentially facilitated by the interactions of the viral RNA with G3BP1 as well as the viral capsid protein with G3BP1 and Caprin-1. Interestingly, expression of capsid proteins from several other flaviviruses also inhibited SG formation. Taken together, the present study provides novel insights into how ZIKV modulates cellular stress response pathways during replication.

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mentioning

confidence: 71%

Zika Virus Hijacks Stress Granule Proteins and Modulates the Host Stress Response

Hou

Kumar

et al. 2017

J Virol

114

132

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“…ZIKV can bind to target cells using adhesion factors such as DC-SIGN and phosphatidylserine binding receptors (Hamel et al, 2017) from which Axl appeared as the main receptor for the entry in human skin fibroblasts (Hamel et al, 2015), microglia (Meertens et al, 2017), astrocytes (Retallack et al, 2016;Meertens et al, 2017) and blood-brain barrier endothelial cells . Surprisingly, Axl does not seem to be necessary for the entry of ZIKV in NPC and cerebral organoids (Wells et al, 2016;Meertens et al, 2017), despite the high expression of this receptor in NSC and NPC (Cugola et al, 2016;Liu et al, 2016;Nowakowski et al, 2016;Onorati et al, 2016;Meertens et al, 2017). Replication and assembly of progeny virions of ZIKV take place onto modified membranes derived from the endoplasmic reticulum.…”

Section: Mechanisms Of Zikv Entry In Human Cells and The Antiviral Rementioning

confidence: 99%

“…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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“…It has recently been reported that ZIKV entry into cells requires the AXL ligand, Gas6, which bridges the viral particles to glial cells, where the virus is then internalized [29,30]. During the viral entry of the cell, the ZIKV/Gas6 complex activates AXL kinase activity, which dampens the interferon response to the virus and facilitates infection [29,31,32].…”

Section: Aravive-s6mentioning

confidence: 99%

“…During the viral entry of the cell, the ZIKV/Gas6 complex activates AXL kinase activity, which dampens the interferon response to the virus and facilitates infection [29,31,32]. It has recently been reported that Aravive Biologic's engineered decoy AXL receptor, Aravive-S6, can block ZIKV infection by intercepting Gas6 to prevent AXL signaling [29].…”

Section: Aravive-s6mentioning

confidence: 99%