Herpes simplex virus type 1 infection leads to neurodevelopmental disorder-associated neuropathological changes

Neonatal herpes simplex virus type 1 (HSV-1) infections contribute to various neurodevelopmental disabilities and the subsequent long-term neurological sequelae into the adulthood. However, further understanding of fetal brain development and the potential neuropathological effects of the HSV-1 infe...

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Bibliographic Details
Published in:PLoS pathogens 2020-10, Vol.16 (10), p.e1008899-e1008899
Main Authors: Qiao, Haowen, Guo, Moujian, Shang, Jia, Zhao, Wen, Wang, Zhenyan, Liu, Nian, Li, Bin, Zhou, Ying, Wu, Ying, Chen, Pu
Format: Article
Language:English
Subjects:
Biology and Life Sciences
Biomedical engineering
Brain
Brain - pathology
Brain - virology
Brain research
Care and treatment
Cell differentiation
Cell Differentiation - physiology
Complications and side effects
Development and progression
Differentiation
Disabilities
Encephalitis
Engineering
Fetuses
Growth factors
Herpes
Herpes simplex
Herpes Simplex - virology
Herpes viruses
Herpesvirus 1, Human - pathogenicity
Herpesvirus diseases
Humans
Hypotheses
Immunology
Induced Pluripotent Stem Cells - cytology
Induced Pluripotent Stem Cells - virology
Infections
Inflammation
Interleukin 10
Interleukin 4
Interleukin 6
Kinases
Laboratories
Learning disabilities
Medicine and Health Sciences
Neonates
Nervous system diseases
Neural stem cells
Neural Stem Cells - cytology
Neural Stem Cells - virology
Neurodevelopment
Neurodevelopmental disorders
Neurodevelopmental Disorders - etiology
Neurodevelopmental Disorders - pathology
Neurodevelopmental Disorders - virology
Neurogenesis
Neurological complications
Neurosciences
Organoids
Pathogenesis
Pathogens
Pluripotency
Research and Analysis Methods
Software
Stem cells
Three dimensional models
Tumor necrosis factor-α
Viral infections
Virology
Viruses
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Summary:Neonatal herpes simplex virus type 1 (HSV-1) infections contribute to various neurodevelopmental disabilities and the subsequent long-term neurological sequelae into the adulthood. However, further understanding of fetal brain development and the potential neuropathological effects of the HSV-1 infection are hampered by the limitations of existing neurodevelopmental models due to the dramatic differences between humans and other mammalians. Here we generated in vitro neurodevelopmental disorder models including human induced pluripotent stem cell (hiPSC)-based monolayer neuronal differentiation, three-dimensional (3D) neuroepithelial bud, and 3D cerebral organoid to study fetal brain development and the potential neuropathological effects induced by the HSV-1 infections. Our results revealed that the HSV-1-infected neural stem cells (NSCs) exhibited impaired neural differentiation. HSV-1 infection led to dysregulated neurogenesis in the fetal neurodevelopment. The HSV-1-infected brain organoids modelled the pathological features of the neurodevelopmental disorders in the human fetal brain, including the impaired neuronal differentiation, and the dysregulated cortical layer and brain regionalization. Furthermore, the 3D cerebral organoid model showed that HSV-1 infection promoted the abnormal microglial activation, accompanied by the induction of inflammatory factors, such as TNF-α, IL-6, IL-10, and IL-4. Overall, our in vitro neurodevelopmental disorder models reconstituted the neuropathological features associated with HSV-1 infection in human fetal brain development, providing the causal relationships that link HSV biology with the neurodevelopmental disorder pathogen hypothesis.
ISSN:1553-7374
1553-7366
1553-7374
DOI:10.1371/journal.ppat.1008899