Flavivirus Cell Entry and Membrane Fusion

Smit, Jolanda M.; Moesker, Bastiaan; Rodenhuis-Zybert, Izabela A.; Wilschut, Jan

doi:10.3390/v3020160

Cited by 258 publications

(223 citation statements)

References 87 publications

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“…When cholesterol is added to the flies' diet, DCV grows to lethal titers in the presence of Wolbachia (37). Cholesterol is important for several steps in flavivirus infection, including entry early in infection (38). To determine if the Drosophila observed phenotype translates to a human pathogen, we investigated if the addition of cholesterol would rescue ZIKV growth in Wolbachia.…”

Section: Resultsmentioning

confidence: 99%

Variable Inhibition of Zika Virus Replication by Different Wolbachia Strains in Mosquito Cell Cultures

Schultz

Isern

Michael

et al. 2017

J Virol

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Mosquito-borne arboviruses are a major source of human disease. One strategy to reduce arbovirus disease is to reduce the mosquito's ability to transmit virus. Mosquito infection with the bacterial endosymbiont Wolbachia pipientis wMel is a novel strategy to reduce Aedes mosquito competency for flavivirus infection. However, experiments investigating cyclic environmental temperatures have shown a reduction in maternal transmission of wMel, potentially weakening the integration of this strain into a mosquito population relative to that of other Wolbachia strains. Consequently, it is important to investigate additional Wolbachia strains. All Zika virus (ZIKV) suppression studies are limited to the wMel Wolbachia strain. Here we show ZIKV inhibition by two different Wolbachia strains: wAlbB (isolated from Aedes albopictus mosquitoes) and wStri (isolated from the planthopper Laodelphax striatellus) in mosquito cells. Wolbachia strain wStri inhibited ZIKV most effectively. Singlecycle infection experiments showed that ZIKV RNA replication and nonstructural protein 5 translation were reduced below the limits of detection in wStri-containing cells, demonstrating early inhibition of virus replication. ZIKV replication was rescued when Wolbachia was inhibited with a bacteriostatic antibiotic. We observed a partial rescue of ZIKV growth when Wolbachia-infected cells were supplemented with cholesterol-lipid concentrate, suggesting competition for nutrients as one of the possible mechanisms of Wolbachia inhibition of ZIKV. Our data show that wAlbB and wStri infection causes inhibition of ZIKV, making them attractive candidates for further in vitro mechanistic and in vivo studies and future vector-centered approaches to limit ZIKV infection and spread.IMPORTANCE Zika virus (ZIKV) has swiftly spread throughout most of the Western Hemisphere. This is due in large part to its replication in and spread by a mosquito vector host. There is an urgent need for approaches that limit ZIKV replication in mosquitoes. One exciting approach for this is to use a bacterial endosymbiont called Wolbachia that can populate mosquito cells and inhibit ZIKV replication. Here we show that two different strains of Wolbachia, wAlbB and wStri, are effective at repressing ZIKV in mosquito cell lines. Repression of virus growth is through the inhibition of an early stage of infection and requires actively replicating Wolbachia. Our findings further the understanding of Wolbachia viral inhibition and provide novel tools that can be used in an effort to limit ZIKV replication in the mosquito vector, thereby interrupting the transmission and spread of the virus.KEYWORDS Wolbachia, Zika virus, arthropod vectors, vector biology

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Section: Resultsmentioning

confidence: 99%

Variable Inhibition of Zika Virus Replication by Different Wolbachia Strains in Mosquito Cell Cultures

Schultz

Isern

Michael

et al. 2017

J Virol

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“…Members of the Flaviviridae family, including important human pathogens like Dengue, West Nile virus (WNV), hepatitis C virus (HCV), and the recently pandemic Zika virus, all enter via receptor-mediated or clathrin-mediated endocytosis [31,64,65]. HCV, Dengue, WNV and Zika virus then enter late endosomes after Bback-fusion^of ILVs with this compartment, at which point the viral genome is dumped into the cytoplasm [66,67].…”

Section: Viral Manipulation Of Exosomal Pathwaymentioning

confidence: 99%

Exosomes in Viral Disease

2016

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Viruses have evolved many mechanisms by which to evade and subvert the immune system to ensure survival and persistence. However, for each method undertaken by the immune system for pathogen removal, there is a counteracting mechanism utilized by pathogens. The new and emerging role of microvesicles in immune intercellular communication and function is no different. Viruses across many different families have evolved to insert viral components in exosomes, a subtype of microvesicle, with many varying downstream effects. When assessed cumulatively, viral antigens in exosomes increase persistence through cloaking viral genomes, decoying the immune system, and even by increasing viral infection in uninfected cells. Exosomes therefore represent a source of viral antigen that can be used as a biomarker for disease and targeted for therapy in the control and eradication of these disorders. With the rise in the persistence of new and reemerging viruses like Ebola and Zika, exploring the role of exosomes become more important than ever.

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“…The E proteins insert their fusion loops into the outer leaflet of the cell membrane. Three E monomers interact with one another via their fusion loops to form an unstable trimer which is stabilized through additional interactions between the DI domains of the three E proteins [50,64]. Next, DIII is believed to fold back against the trimer to form a hairpin-like configuration.…”

Section: Replication Cyclementioning

confidence: 99%

“…The first step in the infectious cell entry involves the binding of E protein to a cellular molecule-receptor [50]. Several cell molecules have been proven to function as co-receptors for in-vitro virion attachment: WNV interacts with DC-SIGN and DC-SIGN-R in dendritic cells [51].…”

Section: Replication Cyclementioning

confidence: 99%