Expression Analysis Highlights AXL as a Candidate Zika Virus Entry Receptor in Neural Stem Cells

Nowakowski, Tomasz J.; Pollen, Alex A.; Lullo, Elizabeth Di; Sandoval-Espinosa, Carmen; Bershteyn, Marina; Kriegstein, Arnold R.

doi:10.1016/j.stem.2016.03.012

Cited by 496 publications

(492 citation statements)

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“…We reasoned that identifying cell types that are especially vulnerable to viral infection would facilitate studies of the viral life cycle, including entry mechanisms and host cell requirements. Building on studies that suggested that enriched expression of the candidate entry factor AXL could confer vulnerability to ZIKV entry (6-8), we used AXL expression levels to predict that radial glia, astrocytes, microglia, and endothelial cells would be particularly vulnerable to infection (9). A recent study highlighted the utility of ex vivo models using primary human tissue samples to analyze the consequences of ZIKV infection in the human prenatal brain (7).…”

mentioning

confidence: 99%

Zika virus cell tropism in the developing human brain and inhibition by azithromycin

Retallack

Lullo

Arias

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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465

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The rapid spread of Zika virus (ZIKV) and its association with abnormal brain development constitute a global health emergency. Congenital ZIKV infection produces a range of mild to severe pathologies, including microcephaly. To understand the pathophysiology of ZIKV infection, we used models of the developing brain that faithfully recapitulate the tissue architecture in early to midgestation. We identify the brain cell populations that are most susceptible to ZIKV infection in primary human tissue, provide evidence for a mechanism of viral entry, and show that a commonly used antibiotic protects cultured brain cells by reducing viral proliferation. In the brain, ZIKV preferentially infected neural stem cells, astrocytes, oligodendrocyte precursor cells, and microglia, whereas neurons were less susceptible to infection. These findings suggest mechanisms for microcephaly and other pathologic features of infants with congenital ZIKV infection that are not explained by neural stem cell infection alone, such as calcifications in the cortical plate. Furthermore, we find that blocking the glia-enriched putative viral entry receptor AXL reduced ZIKV infection of astrocytes in vitro, and genetic knockdown of AXL in a glial cell line nearly abolished infection. Finally, we evaluate 2,177 compounds, focusing on drugs safe in pregnancy. We show that the macrolide antibiotic azithromycin reduced viral proliferation and virusinduced cytopathic effects in glial cell lines and human astrocytes. Our characterization of infection in the developing human brain clarifies the pathogenesis of congenital ZIKV infection and provides the basis for investigating possible therapeutic strategies to safely alleviate or prevent the most severe consequences of the epidemic.A correlation between congenital exposure to the mosquitoborne and sexually transmitted Zika flavivirus (ZIKV) and the increased incidence of severe microcephaly suggests a causal relationship between ZIKV infection and neurodevelopmental abnormalities (1, 2). However, the mechanisms of infection and specifically which cell populations are vulnerable to ZIKV during the course of human brain development remain unclear. Major insights have been drawn from in vitro models of human brain development and primary mouse tissues. In the developing mouse brain, ZIKV has been shown to infect radial glia and neurons (3), whereas studies in human pluripotent stem cell (hPSC)-derived neural cells have highlighted widespread infection and apoptosis of neural progenitor cells (4,5). Because these models do not fully recapitulate the developmental events and cell types present during human brain development, these results may not faithfully represent ZIKV-induced pathology in vivo.During human brain development, radial glial cells, the neural stem cells, give rise to diverse types of neuronal and glial cells, including neurons, oligodendrocytes, and astrocytes, in a temporally controlled pattern. We reasoned that identifying cell types that are especially vulnerable to viral infection wou...

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confidence: 99%

Zika virus cell tropism in the developing human brain and inhibition by azithromycin

Retallack

Lullo

Arias

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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465

393

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“…Con base en los resultados de estudios en cultivos celulares, Nowakowski, et al (41), han sugerido que los virus ZIKV, DENV y WNV pueden requerir receptores TAM para su fijación o entrada, y que la Axl actuaría como proteína de unión y receptor de entrada. La caracterización de la expresión de Axl en células madre neuronales fue el primer paso en la identificación de uno de los candidatos a ser el receptor de entrada del ZIKV (41). Se ha detectado este receptor Axl, con actividad tirosina cinasa, en la señalización mediada por los receptores TLR (toll like receptors), y resulta pertinente anotar que la vía de señalización TLR3 se ha asociado con el daño celular inducido por el ZIKV, lo cual sugiere una relación entre el receptor Axl y la patogenia del Zika (42).…”

Section: Discussionunclassified

Características de la estructura molecular de las proteínas E del virus Zika y E1 del virus de la rubeola. Posibles implicaciones en el neurotropismo y en las alteraciones del sistema nervioso

et al. 2016

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: concepción y formulación de la hipótesis, planteamiento del objetivo y la pregunta de investigación, obtención de las estructuras moleculares, interpretación y discusión de los resultados Gladis Montoya: obtención de las estructuras moleculares Todos los autores participaron en el análisis comparativo de resultados y la escritura del manuscrito.Características de la estructura molecular de las proteínas E del virus del Zika y E1 del virus de la rubéola y posibles implicaciones en el neurotropismo y en las alteraciones del sistema nervioso Introducción. El virus del Zika (ZIKV) es un flavivirus con envoltura, transmitido a los seres humanos principalmente por el vector Aedes aegypti. La infección por ZIKV se ha asociado con un gran neurotropismo y con efectos neuropáticos, como el síndrome de Guillain-Barré en el adulto y la microcefalia fetal y posnatal, así como con un síndrome de infección congénita similar al producido por el virus de la rubéola (RV).Objetivo. Comparar las estructuras moleculares de la proteína de envoltura E del virus del Zika (E-ZIKV) y de la E1 del virus de la rubéola (E1-RV), y plantear posibles implicaciones en el neurotropismo y en las alteraciones del sistema nervioso asociadas con el ZIKV. Materiales y métodos. La secuencia de aminoácidos de la proteína E-ZIKV (PDB: 5iZ7) se alineó con la de la glucopreteína E1 del virus de la rubéola (PDB: 4ADG). Los elementos de la estructura secundaria se determinaron usando los programas Vector NTI Advance ® , DSSP y POSA, así como herramientas de gestión de datos (AlignX ® ). Uno de los criterios principales de comparación y alineación fue la asignación de residuos estructuralmente equivalentes, con más de 70 % de identidad.Resultados. La organización estructural de la proteína E-ZIKV (PDB: 5iZ7) fue similar a la de E1-RV (PDB: 4ADG) (70 a 80 % de identidad), y se observó una correspondencia con la estructura definida para las glucoproteínas de fusión de membrana de clase II de los virus con envoltura. E-ZIKV y E1-RV exhibieron elementos estructurales de fusión muy conservados en la región distal del dominio II, asociados con la unión a los receptores celulares de entrada del virus de la rubéola (glucoproteína de mielina del oligodendrocito, Myelin Oligodendrocyte Glycoprotein, MOG), y con los receptores celulares Axl del ZIKV y de otros flavivirus. Conclusión. La comparación de las proteínas E-ZIKV y E1-RV es un paso necesario hacia la definición de otros factores moleculares determinantes del neurotropismo y la patogenia del ZIKV, el cual puede contribuir a generar estrategias de diagnóstico, prevención y tratamiento de las complicaciones neurológicas inducidas por el ZIKV.Palabras clave: virus Zika; virus de la rubéola; estructura molecular; microcefalia; glucoproteína de la mielina del oligodendrocito. Materials and methods:The amino acid sequence of E-ZIKV protein (PDB: 5iZ7) was aligned to that of rubella virus glycoprotein E1 (PDB: 4ADG). The secondary structure elements were determined using the programs Vector NTI Advance®, DSSP, and ...

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“…Several research groups applied the brain organoid model to study Zika infection, a current epidemic that has been strongly linked to newborn microcephaly 35, 46, 47, 48, 49, 50. These studies have provided evidence that human neural stem cells are selectively vulnerable35, 48 and more susceptible to premature differentiation50 upon Zika virus infection, providing a molecular explanation for the observed microcephaly.…”

Section: Translational Applications Of Brain Organoidsmentioning

confidence: 99%

“…A further study suggested activation of innate immune responses as a possible mechanism for Zika‐induced neuroprogenitor cell death 47. In addition, organoid model has been used to identify putative receptor proteins mediating Zika entry into the nervous system 49. Most recently, brain organoids were used to validate potential repurposed drugs for treating Zika infections 51…”

Section: Translational Applications Of Brain Organoidsmentioning

confidence: 99%

Translational potential of human brain organoids

Sun

Tan

2018

Ann Clin Transl Neurol

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The recent technology of 3D cultures of cellular aggregates derived from human stem cells have led to the emergence of tissue‐like structures of various organs including the brain. Brain organoids bear molecular and structural resemblance with developing human brains, and have been demonstrated to recapitulate several physiological and pathological functions of the brain. Here we provide an overview of the development of brain organoids for the clinical community, focusing on the current status of the field with an critical evaluation of its translational value.

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Expression Analysis Highlights AXL as a Candidate Zika Virus Entry Receptor in Neural Stem Cells

Cited by 496 publications

References 46 publications

Zika virus cell tropism in the developing human brain and inhibition by azithromycin

Zika virus cell tropism in the developing human brain and inhibition by azithromycin

Características de la estructura molecular de las proteínas E del virus Zika y E1 del virus de la rubeola. Posibles implicaciones en el neurotropismo y en las alteraciones del sistema nervioso

Translational potential of human brain organoids

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