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The mitotic spindle: linking teratogenic effects of Zika virus with human genetics?

ABSTRACT: BACKGROUND:Recently, an association between Zika virus infection and microcephaly/ocular findings was found to be reasonable e.g. because of the demonstration that the virus was found in the brain of a fetus after presumed maternal infection. Although there is no proof yet for a causal relationship, for an appropriate risk calculation efforts are urgently needed to either establish or disprove this assumption. PRESENTATION OF THE HYPOTHESIS:On the basis of inherited syndromes combining microcephaly with ocular findings similar to those associated with Zika infections, we have hypothesized that the impairment of the proper function of the mitotic apparatus is a possible mechanism by which Zika can exert teratogenic effects. TESTING THE HYPOTHESIS:A bundle of well-known cytogenetic and molecular-cytogenetic methods (e.g. formation of micronuclei, chromosomal lagging, immunofluorescence of centrosomes) to evaluate proper function, maintenance, and establishment of the mitotic spindle poles can be applied on infected cells. Also, the viral proteins can be tested for their possible interaction with proteins encoded by genes involved in inherited syndromes with microcephaly and ocular findings resembling those in presumed cases of intrauterine ZIKV infection. IMPLICATIONS OF THE HYPOTHESIS:Once proved, this hypothesis allows for a targeted approach into mechanisms of possible relevance as e.g. if different strains of the virus are implicated in the teratogenic effects to the same or a different extent.

SUBMITTER: Bullerdiek J

PROVIDER: S-EPMC4837584 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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The mitotic spindle: linking teratogenic effects of Zika virus with human genetics?

Bullerdiek Joern J Dotzauer Andreas A Bauer Ingrid I

Molecular cytogenetics 20160419

<h4>Background</h4>Recently, an association between Zika virus infection and microcephaly/ocular findings was found to be reasonable e.g. because of the demonstration that the virus was found in the brain of a fetus after presumed maternal infection. Although there is no proof yet for a causal relationship, for an appropriate risk calculation efforts are urgently needed to either establish or disprove this assumption.<h4>Presentation of the hypothesis</h4>On the basis of inherited syndromes comb ...[more]

PMID: 27099632

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Project description:Zika virus (ZIKV), a mosquito-borne flavivirus discovered in 1947, has only recently caused large outbreaks and emerged as a significant human pathogen. In 2015, ZIKV was detected in Brazil, and the resulting epidemic has spread throughout the Western Hemisphere. Severe complications from ZIKV infection include neurological disorders such as Guillain-Barré syndrome in adults and a variety of fetal abnormalities, including microcephaly, blindness, placental insufficiency, and fetal demise. There is an urgent need for tools and reagents to study the pathogenesis of epidemic ZIKV and for testing vaccines and antivirals. Using a reverse genetics platform, we generated six ZIKV infectious clones and derivative viruses representing diverse temporal and geographic origins. These include three versions of MR766, the prototype 1947 strain (with and without a glycosylation site in the envelope protein), and H/PF/2013, a 2013 human isolate from French Polynesia representative of the virus introduced to Brazil. In the course of synthesizing a clone of a circulating Brazilian strain, phylogenetic studies identified two distinct ZIKV clades in Brazil. We reconstructed viable clones of strains SPH2015 and BeH819015, representing ancestral members of each clade. We assessed recombinant virus replication, binding to monoclonal antibodies, and virulence in mice. This panel of molecular clones and recombinant virus isolates will enable targeted studies of viral determinants of pathogenesis, adaptation, and evolution, as well as the rational attenuation of contemporary outbreak strains to facilitate the design of vaccines and therapeutics.IMPORTANCE Viral emergence is a poorly understood process as evidenced by the sudden emergence of Zika virus in Latin America and the Caribbean. Malleable reagents that both predate and span an expanding epidemic are key to understanding the virologic determinants that regulate pathogenesis and transmission. We have generated representative cDNA molecular clones and recombinant viruses that span the known ZIKV family tree, including early Brazilian isolates. Recombinant viruses replicated efficiently in cell culture and were pathogenic in immunodeficient mice, providing a genetic platform for rational vaccine and therapeutic design.

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The mitotic spindle: linking teratogenic effects of Zika virus with human genetics?

Publications

The mitotic spindle: linking teratogenic effects of Zika virus with human genetics?

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