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To advance the translational potential of organoid- Viral infections during fetal development significantly
based research, several critical hurdles must be addressed contribute to various neurological deficits, including
as priorities, including the development of standardized microcephaly, encephalitis, seizures, and cognitive
differentiation protocols, the incorporation of vascular impairments (Figure 5). These infections disrupt critical
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and immune system components, and the integration developmental processes by impairing neural progenitor
of machine learning algorithms to unify genomic, function, inducing neuroinflammation, and altering
transcriptomic, and phenotypic data for individualized synaptic connectivity. 271,272 For example, Toxoplasma gondii
therapeutic predictions. In addition, the establishment induces encephalitis and microcephaly, resulting in long-
of collaborative frameworks that connect clinical cohorts term cognitive impairments and developmental delays due
with organoid biobanks holds promise for enhancing the to its impact on neurogenesis and microglial activation.
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precision and translational relevance of disease modeling The rubella virus disrupts neuronal migration and synaptic
and therapeutic discovery. connections, leading to congenital defects such as deafness
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and motor delays. These manifestations underscore the
The convergence of genetic, molecular, and cellular
insights through organoid modeling is reshaping need to understand how specific pathogens influence fetal
our understanding of neurodevelopmental and brain development.
neuropsychiatric disorders. These models not only 3D brain organoid models have revolutionized the
facilitate the investigation of disease pathophysiology but study of viral neuropathogenesis by enabling researchers
also enable the identification and preclinical validation of to accurately simulate infection dynamics and cellular
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novel, mechanism-based therapeutic strategies tailored to responses. For instance, Zika virus infection in organoids
the complex biology of these conditions. demonstrates significant disruption in NPC proliferation
and cortical formation, causing microcephaly and other
8. Unraveling the impact of viral infections developmental defects observed in affected infants.
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on NDDs: Insights from 3D organoid models Human cytomegalovirus alters neuronal differentiation
Environmental factors, particularly viral infections, and cortical layer formation, leading to cognitive deficits
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significantly increase the risk of NDDs such as microcephaly, effectively modeled in organoid systems. The herpes
autism spectrum disorder, and schizophrenia. While the simplex virus disrupts synaptic function and neuronal
placenta acts as a protective barrier, vertical transmission proliferation, offering insights into the mechanisms
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can still occur. Maternal immune activation triggered underlying developmental delays. In addition,
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by infections can impact fetal development at any stage of enterovirus 71 (EV71) infection results in acute flaccid
pregnancy. Viral infections during gestation have been paralysis and encephalitis, with organoids revealing how
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associated with various congenital neurological defects; EV71 induces neuronal damage and disrupts neurogenesis
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however, the mechanisms by which pathogens cross the through neuroinflammatory pathways.
placental barrier remain poorly understood, primarily due Chikungunya virus also causes neuroinflammation and
to the lack of model systems that accurately replicate human cognitive impairment, with organoids elucidating how this
brain development while integrating maternal factors. The inflammation affects neural precursor cells and normal
advent of 3D organoid models has significantly advanced brain development. Similarly, West Nile virus impacts
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research on maternal and fetal viral infections, providing neuronal maturation and synaptic plasticity, while
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deeper insights into their effects on brain development. 266,267 influenza virus affects neurogenesis, both resulting in long-
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The “TORCH” acronym originally referred to term cognitive impairments and motor dysfunction.
Toxoplasma gondii, rubella virus, human cytomegalovirus, The neurodevelopmental implications of coronavirus
and herpes simplex virus, but was later expanded to include disease 2019 (COVID-19; caused by SARS-CoV-2) are still
additional pathogens, sometimes referred to as “STORCH” emerging, but organoid models are proving essential for
to incorporate syphilis. Emerging infectious agents, such understanding its potential effects on neural differentiation
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as the Zika virus and severe acute respiratory syndrome and cognitive function.
coronavirus 2 (SARS-CoV-2), continue to reshape this Overall, 3D organoid models serve as a crucial platform
classification. TORCH pathogens are known to cause for dissecting the cellular and molecular mechanisms
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a range of congenital abnormalities, including heart underlying the effects of these viral pathogens on brain
malformations, eye defects, pneumonia, brain calcifications, development. By providing insights into host-pathogen
and microcephaly, affecting multiple organ systems. interactions and the specific disruptions caused by
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They are also linked to intrauterine growth restriction, various viruses, these models enhance our understanding
miscarriages, and stillbirths, primarily transmitted to the of congenital viral infections and their long-term
fetus through vertical transmission, either transplacental or consequences, ultimately guiding potential therapeutic
during birth. interventions to mitigate their impact on future generations.

Volume 1 Issue 3 (2025) 17 doi: 10.36922/OR025100010