Complete Genome Sequences of Three Historically Important, Spatiotemporally Distinct, and Genetically Divergent Strains of Zika Virus: MR-766, P6-740, and PRVABC-59

Yun, Sijung; Song, Beom-Heon; Frank, Jordan C.; Julander, Justin G.; Polejaeva, Irina A.; Davies, Christopher J.; White, Kenneth L.; Lee, Young-Min

doi:10.1128/genomea.00800-16

Cited by 35 publications

(34 citation statements)

References 59 publications

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“…However, the prototype ZIKV strain, MR766, is an African-lineage strain isolated from a sentinel rhesus macaque in 1947 and subsequently maintained by extensive passage in suckling mouse brains (ϳ150 passages) (46). Likely due to this long history, several variants of MR766 have been used by different groups, and nonidentical sequences deposited in NCBI (47,48). Among the many differences in reference sequences for ZIKV strains named "MR766" is the glycosylation signal at N154, with some sequences encoding an intact glycosylation signal (accession number HQ234498.1), some with a T-to-I point mutation that ablates the glycosylation signal (accession number LC002520.1), and others with a 4-to 6-amino-acid deletion that ablates the glycosylation signal (accession numbers DQ859059.1, AY632535.2, and NC_012532.1).…”

Section: Ifnar1 -/-Subcutaneous Infectionmentioning

confidence: 99%

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Envelope Protein Glycosylation Mediates Zika Virus Pathogenesis

Carbaugh

Baric

Lazear

2019

J Virol

105

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Zika virus (ZIKV) is an emerging mosquito-borne flavivirus. Recent ZIKV outbreaks have produced serious human disease, including neurodevelopmental malformations (congenital Zika syndrome) and Guillain-Barré syndrome. These outcomes were not associated with ZIKV infection prior to 2013, raising the possibility that viral genetic changes could contribute to new clinical manifestations. All contemporary ZIKV isolates encode an N-linked glycosylation site in the envelope (E) protein (N154), but this glycosylation site is absent in many historical ZIKV isolates. Here, we investigated the role of E protein glycosylation in ZIKV pathogenesis using two contemporary Asian-lineage strains (H/PF/2013 and PRVABC59) and the historical African-lineage strain (MR766). We found that glycosylated viruses were highly pathogenic in Ifnar1 Ϫ/Ϫ mice. In contrast, nonglycosylated viruses were attenuated, producing lower viral loads in the serum and brain when inoculated subcutaneously but remaining neurovirulent when inoculated intracranially. These results suggest that E glycosylation is advantageous in the periphery but not within the brain. Accordingly, we found that glycosylation facilitated infection of cells expressing the lectins dendritic cell-specific intercellular adhesion molecule-3-grabbing nonintegrin (DC-SIGN) or DC-SIGN-related (DC-SIGNR), suggesting that inefficient infection of lectin-expressing leukocytes could contribute to the attenuation of nonglycosylated ZIKV in mice. IMPORTANCE It is unclear why the ability of Zika virus (ZIKV) to cause serious disease, including Guillain-Barré syndrome and birth defects, was not recognized until recent outbreaks. One contributing factor could be genetic differences between contemporary ZIKV strains and historical ZIKV strains. All isolates from recent outbreaks encode a viral envelope protein that is glycosylated, whereas many historical ZIKV strains lack this glycosylation. We generated nonglycosylated ZIKV mutants from contemporary and historical strains and evaluated their virulence in mice. We found that nonglycosylated viruses were attenuated and produced lower viral loads in serum and brains. Our studies suggest that envelope protein glycosylation contributes to ZIKV pathogenesis, possibly by facilitating attachment to and infection of lectinexpressing leukocytes.

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Section: Ifnar1 -/-Subcutaneous Infectionmentioning

confidence: 99%

“…ZIKV strains H/PF/2013 and PRVABC59 were provided by the U.S. Centers for Disease Control and Prevention (41,43). The ZIKV MR766 strains were obtained from the World Reference Center for Emerging Viruses and Arboviruses (46)(47)(48). The DENV-3 WHO reference strain (CH54389) was obtained from Aravinda de Silva (UNC) (73).…”

Section: Cells and Virusesmentioning

confidence: 99%

Envelope Protein Glycosylation Mediates Zika Virus Pathogenesis

Carbaugh

Baric

Lazear

2019

J Virol

105

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“…H/PF/2013 (a 2013 human isolate from French Polynesia) causes 100% lethality in Ifnar1 −/− mice (2, 13). MR766 is the prototype ZIKV strain and has been passaged ∼150 times through suckling mouse brains, which could result in mouse-adaptive mutations (14-16). However, the MR766 variant used in these studies contains a 4 amino acid deletion ablating an N-linked glycosylation site in the viral envelope protein, resulting in a virus that is less virulent in Ifnar1 −/− mice compared to H/PF/2013 (2, 17).…”

Section: Resultsmentioning

confidence: 99%

Zika virus infection in Collaborative Cross mice

Mattocks

Plante

Fritch

et al. 2019

Preprint

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14The 2015-2016 emergence of Zika virus (ZIKV) in the Americas, and recognition that ZIKV 15 infection during pregnancy can result in birth defects, revealed a need for small animal models to 16 study ZIKV pathogenic mechanisms and evaluate candidate vaccines and antivirals. Mice would 17 be an attractive system for such studies, but ZIKV replicates poorly in laboratory mice because it 18 fails to antagonize murine STAT2 and STING. To address this, most ZIKV pathogenesis studies 19 have used mice with impaired interferon signaling (e.g. Ifnar1 -/or treatment with IFNAR1-blocking 20 antibodies). However, using mice with severe defects in innate antiviral signaling confounds 21 studies of viral pathogenic mechanisms. Collaborative Cross (CC) mice have proven to be a 22valuable system for developing new mouse pathogenesis models for viral infections that are not 23 well modeled in conventional laboratory mouse lines. To test whether CC mice could provide an 24 immune-competent model for ZIKV pathogenesis, we infected CC lines with ZIKV and assessed 25 weight loss, viremia, and production of neutralizing antibodies. We tested 21 CC lines (CC001, 26 All rights reserved. No reuse allowed without permission.

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“…Genome analysis of three ZIKV strains; MR‐766 (African lineage, Uganda 1947), P6‐740 (Asian lineage, Malaysia 1966), and PRVABC59 (Asian lineage‐derived American strain, Puerto Rico, 2015) revealed that the gRNA is 10, 807 nts (nucleotides) in length, with a single 10, 272‐nt open reading frame (ORF) flanked by noncoding regions or UTRs (untranslated regions) . The 5′ UTR is 107 nt long and contains the viral promoter while the 3′ UTR is 428 nt long, lacks a polyadenylated tail and ends in CU OH . The UTRs also contain conserved stem loop like RNA structures that may participate in interactions with cellular proteins/nucleic acids of the host.…”

Section: Pathophysiologymentioning

confidence: 99%

Zika virus: Molecular responses and tissue tropism in the mammalian host

Shaily

Upadhya

2019

Reviews in Medical Virology

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Zika virus (ZIKV) outbreaks have raised alarm because of reports of congenital Zika virus syndrome in infants. The virus is also known to cause the debilitating Guillain-Barré syndrome in adults. As a result, extensive research has been carried out on the virus over the past few years. To study the molecular responses of viral infectivity in mammals, in vitro two-dimensional and three-dimensional cellular models have been employed. The in vivo models of mouse, pig, chicken, and nonhuman primates are primarily used to investigate the teratogenicity of the virus, to study effects of the virus on specific tissues, and to study the systemic effects of a proposed antiviral agent. The virus exhibits wide tissue tropism in the mammalian host.

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Complete Genome Sequences of Three Historically Important, Spatiotemporally Distinct, and Genetically Divergent Strains of Zika Virus: MR-766, P6-740, and PRVABC-59

Cited by 35 publications

References 59 publications

Envelope Protein Glycosylation Mediates Zika Virus Pathogenesis

Envelope Protein Glycosylation Mediates Zika Virus Pathogenesis

Zika virus infection in Collaborative Cross mice

Zika virus: Molecular responses and tissue tropism in the mammalian host

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