The Impaired Neurodevelopment of Human Neural Rosettes in HSV-1-Infected Early Brain Organoids.
Leonardo D'AiutoJill K CaldwellCallen T WallaceTristan R GramsMaribeth A WeseskyJoel A WoodSimon C WatkinsPaul R KinchingtonDavid C BloomVishwajit L NimgaonkarPublished in: Cells (2022)
Intrauterine infections during pregnancy by herpes simplex virus (HSV) can cause significant neurodevelopmental deficits in the unborn/newborn, but clinical studies of pathogenesis are challenging, and while animal models can model some aspects of disease, in vitro studies of human neural cells provide a critical platform for more mechanistic studies. We utilized a reductionist approach to model neurodevelopmental outcomes of HSV-1 infection of neural rosettes, which represent the in vitro equivalent of differentiating neural tubes. Specifically, we employed early-stage brain organoids (ES-organoids) composed of human induced pluripotent stem cells (hiPSCs)-derived neural rosettes to investigate aspects of the potential neuropathological effects induced by the HSV-1 infections on neurodevelopment. To allow for the long-term differentiation of ES-organoids, viral infections were performed in the presence of the antiviral drug acyclovir (ACV). Despite the antiviral treatment, HSV-1 infection caused organizational changes in neural rosettes, loss of structural integrity of infected ES-organoids, and neuronal alterations. The inability of ACV to prevent neurodegeneration was associated with the generation of ACV-resistant mutants during the interaction of HSV-1 with differentiating neural precursor cells (NPCs). This study models the effects of HSV-1 infection on the neuronal differentiation of NPCs and suggests that this environment may allow for accelerated development of ACV-resistance.
Keyphrases
- herpes simplex virus
- induced pluripotent stem cells
- endothelial cells
- early stage
- induced apoptosis
- cell cycle arrest
- traumatic brain injury
- pluripotent stem cells
- resting state
- computed tomography
- white matter
- squamous cell carcinoma
- cell death
- cell proliferation
- type diabetes
- brain injury
- magnetic resonance
- climate change
- skeletal muscle
- case control
- sentinel lymph node
- insulin resistance