The Impaired Neurodevelopment of Human Neural Rosettes in HSV-1-Infected Early Brain Organoids
Leonardo D’Aiuto,
Jill K. Caldwell,
Callen T. Wallace,
Tristan R. Grams,
Maribeth A. Wesesky,
Joel A. Wood,
Simon C. Watkins,
Paul R. Kinchington,
David C. Bloom,
Vishwajit L. Nimgaonkar
Affiliations
Leonardo D’Aiuto
Western Psychiatric Institute and Clinic, Department of Psychiatry, School of Medicine, University of Pittsburgh, 3811 O’Hara Street, Pittsburgh, PA 15213, USA
Jill K. Caldwell
Western Psychiatric Institute and Clinic, Department of Psychiatry, School of Medicine, University of Pittsburgh, 3811 O’Hara Street, Pittsburgh, PA 15213, USA
Callen T. Wallace
Department of Cell Biology, School of Medicine, University of Pittsburgh, 3500 Terrace Street, S362 Biomedical Science Tower (South), Pittsburgh, PA 15261, USA
Tristan R. Grams
Academic Research Building, Department of Molecular Genetics and Microbiology, University of Florida, 1200 Newell Drive, R2-231, Gainesville, FL 32610, USA
Maribeth A. Wesesky
Western Psychiatric Institute and Clinic, Department of Psychiatry, School of Medicine, University of Pittsburgh, 3811 O’Hara Street, Pittsburgh, PA 15213, USA
Joel A. Wood
Western Psychiatric Institute and Clinic, Department of Psychiatry, School of Medicine, University of Pittsburgh, 3811 O’Hara Street, Pittsburgh, PA 15213, USA
Simon C. Watkins
Department of Cell Biology, School of Medicine, University of Pittsburgh, 3500 Terrace Street, S362 Biomedical Science Tower (South), Pittsburgh, PA 15261, USA
Paul R. Kinchington
Department of Ophthalmology, University of Pittsburgh, Suite 820, Eye & Ear Building, 203 Lothrop Street, Pittsburgh, PA 15213, USA
David C. Bloom
Academic Research Building, Department of Molecular Genetics and Microbiology, University of Florida, 1200 Newell Drive, R2-231, Gainesville, FL 32610, USA
Vishwajit L. Nimgaonkar
Western Psychiatric Institute and Clinic, Department of Psychiatry, School of Medicine, University of Pittsburgh, 3811 O’Hara Street, Pittsburgh, PA 15213, USA
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.
