Study of the mechanism of protonated histidine-induced conformational changes in the Zika virus dimeric envelope protein using accelerated molecular dynamic simulations

Sun, Jixue; Li, Yang; Pi, Li; Lin, Jianping

doi:10.1016/j.jmgm.2017.04.009

Cited by 11 publications

(10 citation statements)

References 74 publications

(89 reference statements)

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“…The multistep process of membrane fusion that enables ZIKV to infect target cells is pH-induced [ 52 ]. Sun et al [ 59 ] have demonstrated that conserved residues expressed in E protein were protonated under low pH conditions and played key roles in driving the fusion process. While low pH in endosomal compartments enables ZIKV fusion by inducing conformational changes on ZIKV E protein our results suggest that extracellular acidosis enhances the binding of the viral particles to the cell surface thus increasing viral infectivity.…”

Section: Discussionmentioning

confidence: 99%

Extracellular acidosis enhances Zika virus infection both in human cells and ex-vivo tissue cultures from female reproductive tract

Varese

Dantas

Paletta

et al. 2021

Emerging Microbes & Infections

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Zika virus (ZIKV) is a flavivirus transmitted by mosquitoes of the genus Aedes, but unlike other flaviviruses, ZIKV can be sexually transmitted by vaginal intercourse. The healthy vaginal pH ranges from 4.0 to 6.0, reaching values of 6.0 to 7.0 after semen deposition. Here, we report that low extracellular pH values (range 6.2 to 6.6) dramatically increase ZIKV infection on cell lines of different origin including some derived from the female genital tract and monocyte derived macrophages. Furthermore, low pH significantly increased ZIKV infection of human ectocervix and endocervix cultured ex-vivo. Enhancement of infection by low pH was also observed using different ZIKV strains and distinct methods to evaluate viral infection, i.e., plaque assays, RT-PCR, flow cytometry and fluorescence microscopy. Analysis of the mechanisms involved revealed that the enhancement of ZIKV infection induced by low pH was associated with an increased binding of the viral particles to the heparan sulfate expressed on the target cell surface. Acidosis represents a critical but generally overlooked feature of the female genital tract, with major implications for sexual transmission diseases. Our results suggest that low vaginal pH might promote male-tofemale transmission of ZIKV infection.

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Section: Discussionmentioning

confidence: 99%

Extracellular acidosis enhances Zika virus infection both in human cells and ex-vivo tissue cultures from female reproductive tract

Varese

Dantas

Paletta

et al. 2021

Emerging Microbes & Infections

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“…MR766 and MR/PR(prM) showed similar pH stability, with indistinguishable pH versus infectivity profiles (Fig 3E). The 3 amino acid changes in M would thus appear not to influence E-M interactions [83] sufficiently to affect pH stability. In addition, pH stability would not appear to be a determining factor in the reduced virulence of MR/PR(prM) when compared with MR766.…”

Section: Role Of Prm Cleavage or Ph Stability In Virulencementioning

confidence: 99%

Neuroinvasiveness of the MR766 strain of Zika virus in IFNAR-/- mice maps to prM residues conserved amongst African genotype viruses

et al. 2021

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Zika virus (ZIKV) strains are classified into the African and Asian genotypes. The higher virulence of the African MR766 strain, which has been used extensively in ZIKV research, in adult IFNα/β receptor knockout (IFNAR-/-) mice is widely viewed as an artifact associated with mouse adaptation due to at least 146 passages in wild-type suckling mouse brains. To gain insights into the molecular determinants of MR766’s virulence, a series of genes from MR766 were swapped with those from the Asian genotype PRVABC59 isolate, which is less virulent in IFNAR-/- mice. MR766 causes 100% lethal infection in IFNAR-/- mice, but when the prM gene of MR766 was replaced with that of PRVABC59, the chimera MR/PR(prM) showed 0% lethal infection. The reduced virulence was associated with reduced neuroinvasiveness, with MR766 brain titers ≈3 logs higher than those of MR/PR(prM) after subcutaneous infection, but was not significantly different in brain titers of MR766 and MR/PR(prM) after intracranial inoculation. MR/PR(prM) also showed reduced transcytosis when compared with MR766 in vitro. The high neuroinvasiveness of MR766 in IFNAR-/- mice could be linked to the 10 amino acids that differ between the prM proteins of MR766 and PRVABC59, with 5 of these changes affecting positive charge and hydrophobicity on the exposed surface of the prM protein. These 10 amino acids are highly conserved amongst African ZIKV isolates, irrespective of suckling mouse passage, arguing that the high virulence of MR766 in adult IFNAR-/- mice is not the result of mouse adaptation.

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“…Numerous all-atom and CG simulations of the flavivirus envelope have been reported. For example, several all-atom simulation studies investigated viral envelope conformational changes occurring upon exposure to low pH, both during the fusion and maturation processes [26][27][28][29][30][31][32][33][34]. The capacity for individual E/M proteins or their complexes to initiate membrane fusion [35][36][37][38][39][40] and host membrane bending [41] has also been extensively studied via simulation.…”

Section: Simulations Of Flavivirus Systemsmentioning

confidence: 99%

Computational modelling of flavivirus dynamics: The ins and outs

Huber

Marzinek

Boon

et al. 2021

Methods

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Enveloped viruses such as the flaviviruses represent a significant burden to human health around the world, with hundreds of millions of people each year affected by dengue alone. In an effort to improve our understanding of the molecular basis for the infective mechanisms of these viruses, extensive computational modelling approaches have been applied to elucidate their conformational dynamics. Multiscale protocols have been developed to simulate flavivirus envelopes in close accordance with biophysical data, in particular derived from cryo-electron microscopy, enabling high-resolution refinement of their structures and elucidation of the conformational changes associated with adaptation both to host environments and to immunological factors such as antibodies. Likewise, integrative modelling efforts combining data from biophysical experiments and from genome sequencing with chemical modification are providing unparalleled insights into the architecture of the previously unresolved nucleocapsid complex. Collectively, this work provides the basis for the future rational design of new antiviral therapeutics and vaccine development strategies targeting enveloped viruses.

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Study of the mechanism of protonated histidine-induced conformational changes in the Zika virus dimeric envelope protein using accelerated molecular dynamic simulations

Cited by 11 publications

References 74 publications

Extracellular acidosis enhances Zika virus infection both in human cells and ex-vivo tissue cultures from female reproductive tract

Extracellular acidosis enhances Zika virus infection both in human cells and ex-vivo tissue cultures from female reproductive tract

Neuroinvasiveness of the MR766 strain of Zika virus in IFNAR-/- mice maps to prM residues conserved amongst African genotype viruses

Computational modelling of flavivirus dynamics: The ins and outs

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