Unraveling the cellular and molecular dynamics of maternal SARS-CoV-2 infection-induced neurodevelopmental disorders

"Viral infections during pregnancy increase the risk of developing Neurodevelopmental disorders (NDDs) like autism and schizophrenia. Considering emerging viruses worldwide, the field of maternal infection-mediated NDDs is continuously challenged. The offspring of SARS-CoV-2 infected mothers have not yet reached the developmental stage for diagnosing NDDs. However, COVID-19, whether through mother-to-child vertical transmission or virus-associated maternal immune responses (such as the cytokine storm involving microglia and astrocytes), is anticipated to shape the landscape of psychiatric disorders in the years to come. Studies regarding the effect of prenatal exposure to SARS-CoV-2 in autism-like neurobehavioral changes in mice do exist but are still limited. NeuroDevCOVID aims to address this gap through a multi-faceted investigation, including mice transgenic models, behavioral tests, iPSC-derived brain organoids, RNA sequencing, bioinformatics and a human cohort. Specifically, we will: (1) Develop a SARS-CoV-2 MIA mouse model to study offspring pathogenesis using RNA sequencing and behavioral assays; (2) Examine how SARS-CoV-2 spreads in the brain and whether tunneling nanotubes (TNTs) facilitate viral transfer between glial cells and neurons; (3) Investigate SARS-CoV-2's impact on glial-neuron interactions in human brain organoids, focusing on cytokine responses and neuronal function;(4) Compare animal, CNS-iPSC derived cells, and brain organoid findings with neurodevelopmental outcomes in children born to SARS-CoV-2-infected mothers. Specifically, we will develop a SARS-CoV-2 MIA model in mice to investigate unknown pathological mechanisms, with a focus on microglia, key immune cells in brain development. Next, we will explore TNTs as a potential route for SARS-CoV-2 brain invasion. Specifically we will investigate whether maternal SARS-CoV-2 infection spread in the fetal brain via TNTs between microglia and neurons and if this mechanism contribute to long-term neurodevelopmental defects. Next, we will use human brain organoids derived from iPSCs, which provide a powerful model for studying SARS-CoV-2 effects on the human brain. We will specifically investigate how glia-neuron interactions shape infection outcomes and what are the long-term neurodevelopmental effects of prenatal SARS-CoV-2 exposure in this model. Last, we will track neurodevelopment in children from SARS-CoV-2-infected pregnancies, providing clinical relevance to the Project. The collaboration between France, Brazil, and Greece combines complementary expertise: France (Team A), expert biologist in membrane trafficking in 2D and 3D culture models leads research on tunneling nanotubes (TNTs) and viral spread, providing key insights into SARS-CoV-2 neurotropism. Brazil (Teams B & D) specializes in patient-derived iPSCs, brain organoids, and longitudinal cohort studies, following 550+ children from 3 months to 3 years old to assess neurodevelopmental outcomes. Greece (Team C) contributes expertise in microglial function and neuroinflammation, essential for understanding maternal immune activation-driven NDD risks. NeuDevCOVID is anticipated to discover novel brain cellular and intercellular communication mechanisms that may act as driving forces for cognitive disabilities in patients with maternal SARS-CoV-2 infection-mediated NDDs and thus could be of clinical relevance and potential targets for therapeutic purposes. Globally, it aligns with international priorities on post-COVID neurological effects, integrating innovative models (mouse, brain organoids, iPSCs) with human cohort data to ensure broad applicability across populations. It is also anticipated to pave the way for surveying possible health implications that may arise from any virus that may emerge in the future worldwide and has mother-to-child transmission direct complications in early life or manifest as behavioral changes in later life. Last, its international nature is also expected to inspire future multinational collaborations and consortiums in favor of the global need for tackling the effects of emerging infectious diseases and their comorbidities to human health."