Pluripotent stem cells-derived 2D and 3D neural models as a platform to investigate Human Cytomegalovirus (HCMV) neuropathogenesis and potential pharmacological treatments

Human cytomegalovirus (HCMV) is a member of the Herpesviridae family. It is an opportunistic infectious agent, which becomes latent in the host after primary infection. HCMV is the most common cause of congenital infections (cCMV) and can induce severe complications in immunocompromised patients. The aim of this study was to characterize HCMV infection in pluripotent stem cells-derived Neural Stem Cells (NSCs) and in induced neurons (iNeurons) to study the neuroprotective activity of antiviral drugs, such as ganciclovir, letermovir, nitazoxanide, and OZ418, as potential treatments against cCMV. Moreover, we optimized a 3D platform of cerebral organoids that can recapitulate the early-developing human brain and that can be exploited to study the effects of HCMV infection, comparing those effects with the ones detected upon drug treatment. In this study, we observed a pattern of disruption of key markers implicated in neurogenesis during HCMV infection and neuroprotection activity of specific antiviral drugs. Overall, NSCs, differentiating neurons, and cerebral organoids represent a valuable platform to study cCMV, since they represent the natural target of the infection in vivo and can recapitulate the differentiation stages of cells in the developing brain.