The Development of a Novel Human Pluripotent Stem Cell-Based Organoid System to Study Host-Virus interactions in the Central Nervous System
Herpes simplex virus (HSV-1) is a common virus that in rare cases invades the central nervous system (CNS), causing a devastating and potentially lethal viral encephalitis. Herpes simplex encephalitis is the most common sporadic viral encephalitis in Western countries and despite antiviral therapy survivors often suffer from severe neurological deficits.
For many neurotropic viruses, including HSV-1, it is not fully understood which receptors enable viral entry, which host antiviral factors are crucial for CNS cell-intrinsic immunity, or what mechanisms underlie chronic inflammation and long-term neurological deficits. Advancements in human pluripotent stem cell (hPSC) technology offer a unique opportunity to the neuroimmunology field to study host-virus interactions in human, disease relevant cells of the CNS. This project will focus on the development of a novel hPSC-based organoid fusion model to study the molecular mechanisms underlying acute viral infection, the establishment of viral latency, and the temporal dynamics of viral spread of HSV-1 throughout different compartments of the human nervous system. Differentiation of hPSCs into region-specific organoids will be achieved through careful patterning using small molecules and morphogens and characterized by the use of hPSC reporter lines, high-resolution imaging, and single cell genomics. Subsequent tissue engineering will allow the fusion of multiple organoids to generate complex 3D-models to study host-virus interactions in a human, disease-relevant background.