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Interplay Between Zika Virus-Induced Autophagy and Neural Stem Cell Fate Determination

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Abstract

The Zika virus (ZIKV) outbreaks and its co-relation with microcephaly have become a global health concern. It is primarily transmitted by a mosquito, but can also be transmitted from an infected mother to her fetus causing impairment in brain development, leading to microcephaly. However, the underlying molecular mechanism of ZIKV-induced microcephaly is poorly understood. In this study, we explored the role of ZIKV non-structural protein NS4A and NS4B in ZIKV pathogenesis in a well-characterized primary culture of human fetal neural stem cells (fNSCs). We observed that the co-transfection of NS4A and NS4B altered the neural stem cell fate by arresting proliferation and inducing premature neurogenesis. NS4A + NS4B transfection in fNSCs increased autophagy and dysregulated notch signaling. Further, it also altered the regulation of downstream genes controlling cell proliferation. Additionally, we reported that 3 methyl-adenine (3-MA), a potent autophagy inhibitor, attenuated the deleterious effects of NS4A and NS4B as evidenced by the rescue in Notch1 expression, enhanced proliferation, and reduced premature neurogenesis. Our attempts to understand the mechanism of autophagy induction indicate the involvement of mitochondrial fission and ROS. Collectively, our findings highlight the novel role of NS4A and NS4B in mediating NSC fate alteration through autophagy-mediated notch degradation. The study also helps to advance our understanding of ZIKV-induced neuropathogenesis and suggests autophagy as a potential target for anti-ZIKV therapeutic intervention.

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Data Availability

All data generated during this study are available from the corresponding author on reasonable request.

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Acknowledgements

We acknowledge the technical assistance from Mr. Naushad Alam and Mr. DL Meena of NBRC. Mr. Naushad also helped in performing some assays. We are thankful to Dr. Shyamala Mani, IISc, India for providing Expression vectors for the Zika virus proteins. We highly acknowledge the fellowship from Council of Scientific and Industrial Research (CSIR) to Bindu and Hriday Shanker Pandey and financial support from NBRC core funds to Prof. Pankaj Seth. We also acknowledge the support of the facilities provided under the Biotechnology Information System Network (BTISNET) grant, Department of Biotechnology (DBT), India, and Distributed Information Centre at NBRC, Manesar, India.

Funding

This study was supported by the Council of Scientific and Industrial Research (CSIR), Department of Biotechnology (DBT), and National Brain Research Centre (NBRC) core fund.

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  1. Department of Cellular and Molecular Neuroscience, Neurovirology Section, National Brain Research Centre, Manesar, Gurgaon, Haryana, 122052, India

    Bindu, Hriday Shanker Pandey & Pankaj Seth

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Contributions

Bindu designed the study, performed experiments, analyzed the data, and wrote the manuscript. Hriday Shanker Pandey helped in performing rescue experiments and writing the manuscript. Pankaj Seth helped in designing experiments, interpretation of data, and finalizing the manuscript.

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Correspondence to Pankaj Seth.

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Strict guidelines of institutional Human ethics and stem cell research committee of NBRC, India in compliance with recommendations of the Indian Council of Medical Research (ICMR) and Department of Biotechnology (DBT), India were followed for isolation of Neural stem cells from aborted human fetus.

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Bindu, Pandey, H.S. & Seth, P. Interplay Between Zika Virus-Induced Autophagy and Neural Stem Cell Fate Determination. Mol Neurobiol (2023). https://doi.org/10.1007/s12035-023-03704-1

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