The pyriproxyfen metabolite, 4′–OH–PPF, disrupts thyroid hormone signaling in neural stem cells, modifying neurodevelopmental genes affected by ZIKA virus infection.

AbstractNorth-Eastern Brazil saw intensive application of the insecticide pyriproxyfen (PPF) during the microcephaly outbreak caused by Zika virus (ZIKV). ZIKV requires the neural RNA-binding protein Musashi-1 to replicate. TH represses MSI1. Being a suspected TH disruptor, we hypothesized that co-exposure to the main metabolite of PPF, 4’-OH-PPF, would exacerbate ZIKV effects through increased MSI1 expression. This was tested using in vitro mouse neurospheres and an in vivo TH signaling reporter model, Xenopus laevis. TH signaling was decreased by 4’-OH-PPF in both models. In mouse-derived neurospheres the metabolite reduced neuroprogenitor proliferation as well as markers of neuronal differentiation. The results demonstrated that 4’-OH-PPF significantly induced MSI1 at both the mRNA and protein level, as well as Fasn mRNA. Other TH target genes were also significantly modified. Importantly, several key genes implicated in neuroprogenitor fate and commitment were not dysregulated by 4’-OH-PPF alone, but were in combination with ZIKV infection. These included the neuroprogenitor markers Nestin, Egfr, Gfap, Dlx2 and Dcx. Unexpectedly, 4’-OH-PPF decreased ZIKV replication, although only at the fourth and last day of incubation, and RNA copy numbers stayed within the same order of magnitude. However, intracellular RNA content of neuroprogenitors was significantly decreased in the combined presence of the PPF metabolite and ZIKV. We conclude that 4’-OH-PPF interferes with TH action in vivo and in vitro, inhibiting neuroprogenitor proliferation. In the presence of ZIKV, TH signaling pathways crucial for cortical development are significantly impacted. This provides another example of viral effects that are exacerbated by drug or pesticide use.Significance statementIn 2015, an increase in children born with unusually small heads (microcephaly) in North-Eastern Brazil was linked to infection with the ZIKA virus. An insecticide with thyroid hormone disruptive properties was used in the same areas. We investigated whether simultaneous exposure to the insecticide could increase viral susceptibility. The main metabolite 4’-OH-PPF dysregulated thyroid hormone signaling pathways crucial for brain development in both models used. Neural stem cells proliferated less and contained more Musashi-1, a protein the virus needs to replicate. Infecting stem cells pre-exposed to the endocrine disruptor did not amplify viral replication, but aggravated expression of genes implicated in brain development. Our results suggest the insecticide is particularly deleterious to brain development in areas with ZIKA virus prevalence.

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Understanding microcephaly through the study of centrosome regulation in Drosophila neural stem cells

Biochemical Society Transactions ◽

10.1042/bst20200261 ◽

2020 ◽

Vol 48 (5) ◽

pp. 2101-2115

Author(s):

Beverly V. Robinson ◽

Victor Faundez ◽

Dorothy A. Lerit

Keyword(s):

Stem Cells ◽

Drosophila Melanogaster ◽

Cell Division ◽

Virus Infection ◽

Neural Stem Cells ◽

Head Circumference ◽

Zika Virus ◽

Asymmetric Cell Division ◽

Significant Proportion ◽

Neuronal Progenitors

Microcephaly is a rare, yet devastating, neurodevelopmental condition caused by genetic or environmental insults, such as the Zika virus infection. Microcephaly manifests with a severely reduced head circumference. Among the known heritable microcephaly genes, a significant proportion are annotated with centrosome-related ontologies. Centrosomes are microtubule-organizing centers, and they play fundamental roles in the proliferation of the neuronal progenitors, the neural stem cells (NSCs), which undergo repeated rounds of asymmetric cell division to drive neurogenesis and brain development. Many of the genes, pathways, and developmental paradigms that dictate NSC development in humans are conserved in Drosophila melanogaster. As such, studies of Drosophila NSCs lend invaluable insights into centrosome function within NSCs and help inform the pathophysiology of human microcephaly. This mini-review will briefly survey causative links between deregulated centrosome functions and microcephaly with particular emphasis on insights learned from Drosophila NSCs.

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Zika Virus Infection of Human Mesenchymal Stem Cells Promotes Differential Expression of Proteins Linked to Several Neurological Diseases

Molecular Neurobiology ◽

10.1007/s12035-018-1417-x ◽

2018 ◽

Vol 56 (7) ◽

pp. 4708-4717 ◽

Cited By ~ 11

Author(s):

Walter O. Beys-da-Silva ◽

Rafael L. Rosa ◽

Lucélia Santi ◽

Markus Berger ◽

Sung Kyu Park ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Virus Infection ◽

Differential Expression ◽

Zika Virus ◽

Neurological Diseases ◽

Human Mesenchymal Stem Cells ◽

Zika Virus Infection

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Memory like NK cells display stem cell like properties after Zika virus infection

PLoS Pathogens ◽

10.1371/journal.ppat.1009132 ◽

2020 ◽

Vol 16 (12) ◽

pp. e1009132

Author(s):

Weshely Kujur ◽

Oscar Murillo ◽

Raju S. R. Adduri ◽

Ramakrishna Vankayalapati ◽

Nagarjun V. Konduru ◽

...

Keyword(s):

Stem Cells ◽

T Cells ◽

Stem Cell ◽

Virus Infection ◽

Nk Cells ◽

Zika Virus ◽

Gene Signature ◽

Hematopoietic Stem ◽

Zika Virus Infection ◽

With Memory

NK cells have been shown to display adaptive traits such as memory formation akin to T and B lymphocytes. Here we show that Zika virus infection induces memory like NK cells that express CD27. Strikingly, these cells exhibit stem-like features that include expansion capacity, self-renewal pathway, differentiation into effector cells, longer telomeres and gene signature associated with hematopoietic stem cell (HSC) progenitors. This subset shared transcriptional and epigenetic changes with memory CD8 T cells, stem cells and stem like T cells. These NK cells with memory and stem cell features, which we term “NK memory stem cells”, demonstrated greater antiviral potential than CD27- or naïve CD27+ NK when adoptively transferred to Zika infected mice. Our results also suggest a role for the transcription factor TCF-1 in memory and stemness features of this NK subset. This study defines a unique TCF1hi CD27+ NK subset with memory capacity and stem cell features that play a role in antiviral immunity.

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Zika virus infection induces MiR34c expression in glioblastoma stem cells: new perspectives for brain tumor treatments

Cell Death and Disease ◽

10.1038/s41419-019-1499-z ◽

2019 ◽

Vol 10 (4) ◽

Cited By ~ 4

Author(s):

Gioacchin Iannolo ◽

Maria Rita Sciuto ◽

Nicola Cuscino ◽

Roberto Pallini ◽

Bruno Douradinha ◽

...

Keyword(s):

Stem Cells ◽

Brain Tumor ◽

Virus Infection ◽

Zika Virus ◽

Glioblastoma Stem Cells ◽

Zika Virus Infection

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Congenital Zika Virus Infection Paradigm: What is in the Wardrobe? A Narrative Review

East Africa Science ◽

10.24248/easci.v1i1.4 ◽

2019 ◽

Vol 1 (1) ◽

pp. 49-56

Author(s):

Mariam M. Mirambo ◽

Lucas Matemba ◽

Mtebe Majigo ◽

Stephen E. Mshana

Keyword(s):

Virus Infection ◽

Neural Tube ◽

Zika Virus ◽

English Language ◽

Case Reports ◽

Case Series ◽

Epidemiological Studies ◽

Ocular Manifestations ◽

Zika Virus Infection ◽

N 93

Background: Zika virus infection during pregnancy has been recently associated with congenital microcephaly and other severe neural tube defects. However, the magnitude of confirmed cases and the scope of these anomalies have not been extensively documented. This review focuses on the magnitude of laboratory-confirmed congenital Zika virus cases among probable cases and describing the patterns of congenital anomalies allegedly caused by the Zika virus, information which will inform further research in this area. Methods: We conducted a literature search for English-language articles about congenital Zika virus infection using online electronic databases (PubMed/MEDLINE, POPLINE, Embase, Google Scholar, and Web of Knowledge). The search terms used were, “zika”, “pregnancy”, [year], “microcephaly”, “infants”, “children”, “neonates”, “foetuses”, “neural tube defect”, and “CNS manifestations” in different combinations. All articles reporting cases or case series between January 2015 and December 2016 were included. Data were entered into a Microsoft Excel database and analysed to obtain proportions of the confirmed cases and patterns of anomalies. Results: A total of 24 articles (11 case series, 9 case reports, and 4 others) were found to be eligible and included in this review. These articles reported 919 cases, with or without microcephaly, presumed to have congenital Zika virus infection. Of these cases, 884 (96.2%) had microcephaly. Of the 884 cases of microcephaly, 783 (88.6%) were tested for Zika virus infection, and 216 (27.6%; 95% confidence interval, 24.5% to 30.8%) were confirmed to be Zika virus-positive. In addition to microcephaly, other common abnormalities reported – out of 442 cases investigated – were calcifications of brain tissue (n=240, 54.3%), ventriculomegaly (n=93, 20.8%), cerebellar hypoplasia (n=52, 11.7%), and ocular manifestations (n=46, 10.4%). Conclusion: Based on the available literature, Zika virus infection during pregnancy might lead to a wide array of outcomes other than microcephaly. There is a need for more epidemiological studies in Zika-endemic areas, particularly in Africa, to ascertain the role of Zika virus in causing congenital neurological defects.

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Congenital Zika Virus Infection Paradigm: What is in the Wardrobe? A Narrative Review

East Africa Science ◽

10.24248/easci.v1.iss1.4 ◽

2019 ◽

Vol 1 (1) ◽

pp. 49-56

Author(s):

Mariam M. Mirambo ◽

Lucas Matemba ◽

Mtebe Majigo ◽

Stephen E. Mshana

Keyword(s):

Virus Infection ◽

Neural Tube ◽

Zika Virus ◽

English Language ◽

Case Reports ◽

Case Series ◽

Epidemiological Studies ◽

Ocular Manifestations ◽

Zika Virus Infection ◽

N 93

Background: Zika virus infection during pregnancy has been recently associated with congenital microcephaly and other severe neural tube defects. However, the magnitude of confirmed cases and the scope of these anomalies have not been extensively documented. This review focuses on the magnitude of laboratory-confirmed congenital Zika virus cases among probable cases and describing the patterns of congenital anomalies allegedly caused by the Zika virus, information which will inform further research in this area. Methods: We conducted a literature search for English-language articles about congenital Zika virus infection using online electronic databases (PubMed/MEDLINE, POPLINE, Embase, Google Scholar, and Web of Knowledge). The search terms used were, “zika”, “pregnancy”, [year], “microcephaly”, “infants”, “children”, “neonates”, “foetuses”, “neural tube defect”, and “CNS manifestations” in different combinations. All articles reporting cases or case series between January 2015 and December 2016 were included. Data were entered into a Microsoft Excel database and analysed to obtain proportions of the confirmed cases and patterns of anomalies. Results: A total of 24 articles (11 case series, 9 case reports, and 4 others) were found to be eligible and included in this review. These articles reported 919 cases, with or without microcephaly, presumed to have congenital Zika virus infection. Of these cases, 884 (96.2%) had microcephaly. Of the 884 cases of microcephaly, 783 (88.6%) were tested for Zika virus infection, and 216 (27.6%; 95% confidence interval, 24.5% to 30.8%) were confirmed to be Zika virus-positive. In addition to microcephaly, other common abnormalities reported – out of 442 cases investigated – were calcifications of brain tissue (n=240, 54.3%), ventriculomegaly (n=93, 20.8%), cerebellar hypoplasia (n=52, 11.7%), and ocular manifestations (n=46, 10.4%). Conclusion: Based on the available literature, Zika virus infection during pregnancy might lead to a wide array of outcomes other than microcephaly. There is a need for more epidemiological studies in Zika-endemic areas, particularly in Africa, to ascertain the role of Zika virus in causing congenital neurological defects.

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