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Molecular Basis of Differential Stability and Temperature Sensitivity of ZIKA versus Dengue Virus Protein Shells.

ABSTRACT: Rapid spread of ZIKA virus (ZIKV) and its association with severe birth defects have raised worldwide concern. Recent studies have shown that ZIKV retains its infectivity and remains structurally stable at temperatures up to 40?°C, unlike dengue and other flaviviruses. In spite of recent cryo-EM structures that showed similar architecture of ZIKA and dengue virus (DENV) E protein shells, little is known that makes ZIKV so temperature insensitive. Here, we attempt to unravel the molecular basis of greater thermal stability of ZIKV over DENV2 by executing atomistic molecular dynamics (MD) simulations on the viral E protein shells at 37?°C. Our results suggest that ZIKA E protein shell retains its structural integrity through stronger inter-raft communications facilitated by a series of electrostatic and H-bonding interactions among multiple inter-raft residues. In comparison, the DENV2 E protein shell surface was loosly packed that exhibited holes at all 3-fold vertices, in close agreement with another EM structure solved at 37?°C. The residue-level information obtained from our study could pave way for designing small molecule inhibitors and specific antibodies to inhibit ZIKV E protein assembly and membrane fusion.

SUBMITTER: Pindi C

PROVIDER: S-EPMC7242387 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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Molecular Basis of Differential Stability and Temperature Sensitivity of ZIKA versus Dengue Virus Protein Shells.

Pindi Chinmai C Chirasani Venkat R VR Rahman Mohammad Homaidur MH Ahsan Mohd M Revanasiddappa Prasanna D PD Senapati Sanjib S

Scientific reports 20200521 1

Rapid spread of ZIKA virus (ZIKV) and its association with severe birth defects have raised worldwide concern. Recent studies have shown that ZIKV retains its infectivity and remains structurally stable at temperatures up to 40 °C, unlike dengue and other flaviviruses. In spite of recent cryo-EM structures that showed similar architecture of ZIKA and dengue virus (DENV) E protein shells, little is known that makes ZIKV so temperature insensitive. Here, we attempt to unravel the molecular basis o ...[more]

PMID: 32439929

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Project description:IntroductionFlaviviruses like dengue virus (DENV) and Zika virus (ZIKV) are mosquito-borne viruses that cause febrile, hemorrhagic, and neurological diseases in humans, resulting in 400 million infections annually. Due to their co-circulation in many parts of the world, flaviviruses must replicate in the presence of pre-existing adaptive immune responses targeted at serologically closely related pathogens, which can provide protection or enhance disease. However, the impact of pre-existing cross-reactive immunity as a driver of flavivirus evolution, and subsequently the implications on the emergence of immune escape variants, is poorly understood. Therefore, we investigated how replication in the presence of convalescent dengue serum drives ZIKV evolution.MethodsWe used an in vitro directed evolution system, passaging ZIKV in the presence of serum from humans previously infected with DENV (anti-DENV) or serum from DENV-naïve patients (control serum). Following five passages in the presence of serum, we performed next-generation sequencing to identify mutations that arose during passaging. We studied two non-synonymous mutations found in the anti-DENV passaged population (E-V355I and NS1-T139A) by generating individual ZIKV mutants and assessing fitness in mammalian cells and live mosquitoes, as well as their sensitivity to antibody neutralization.Results and discussionBoth viruses had increased fitness in Vero cells with and without the addition of anti-DENV serum and in human lung epithelial and monocyte cells. In Aedes aegypti mosquitoes-using blood meals with and without anti-DENV serum-the mutant viruses had significantly reduced fitness compared to wild-type ZIKV. These results align with the trade-off hypothesis of constrained mosquito-borne virus evolution. Notably, only the NS1-T139A mutation escaped neutralization, while E-V335I demonstrated enhanced neutralization sensitivity to neutralization by anti-DENV serum, indicating that neutralization escape is not necessary for viruses passaged under cross-reactive immune pressures. Future studies are needed to assess cross-reactive immune selection in humans and relevant animal models or with different flaviviruses.

Dataset Information

Molecular Basis of Differential Stability and Temperature Sensitivity of ZIKA versus Dengue Virus Protein Shells.

Publications

Molecular Basis of Differential Stability and Temperature Sensitivity of ZIKA versus Dengue Virus Protein Shells.

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