Abstract
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.
Highlights
Neurodevelopmental disorders (NDDs)[1] are a group of conditions that interfere with the central nervous system (CNS) development at an early age
herpes simplex virus type 1 (HSV-1) is one of the most prevalent human pathogens that can spread into the fetal central nervous system by maternal-fetal transmission, and resulting in long-term
The human induced pluripotent stem cell (hiPSC) could be infected by Herpes simplex virus (HSV)-1, but the infection was only limited to a fraction of cells at the colony edge (S1B Fig)
Summary
Neurodevelopmental disorders (NDDs)[1] are a group of conditions that interfere with the central nervous system (CNS) development at an early age. HSV is categorized into 2 types: HSV-1 which is mainly transmitted by oral-to-oral contact to cause oral herpes and cause genital herpes, and HSV-2 which is a sexually transmitted infection that causes genital herpes[9] Both HSV-1 and HSV-2 are highly prevalent and capable of establishing lifelong infection[10]. The risk of maternal transmission of the virus to the fetus or neonate has become a major health concern due to the increased incidence of HSV infections in the pregnant women. The accumulating studies[16] raise the possibility that the fetal HSV-1 infections during pregnancy are associated with risk of neurodevelopmental disorders, result in long-term neurological sequelae, Herpes simplex virus type 1 infection and neurodevelopmental disorder including cognitive dysfunction, learning disabilities, and dementia in adult. The physiological features of the neurodevelopmental disorder associated with HSV-1 infections remain unclear
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