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- Title
The Impaired Neurodevelopment of Human Neural Rosettes in HSV-1-Infected Early Brain Organoids.
- Authors
D'Aiuto, Leonardo; Caldwell, Jill K.; Wallace, Callen T.; Grams, Tristan R.; Wesesky, Maribeth A.; Wood, Joel A.; Watkins, Simon C.; Kinchington, Paul R.; Bloom, David C.; Nimgaonkar, Vishwajit L.
- Abstract
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.
- Subjects
PLURIPOTENT stem cells; NEURAL stem cells; INDUCED pluripotent stem cells; HERPES simplex virus; NEURAL development; ORGANOIDS; NEURONAL differentiation
- Publication
Cells (2073-4409), 2022, Vol 11, Issue 22, p3539
- ISSN
2073-4409
- Publication type
Article
- DOI
10.3390/cells11223539