Human cytomegalovirus dysregulates neurodevelopmental pathways in cerebral organoids
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE217832 | GEO | 2024/03/27
REPOSITORIES: GEO
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Project description:Congenital hearing loss is a common chronic condition affecting children in both developed and developing nations. In many cases, congenital hearing loss is ultimately attributed to viral infection, most often by cytomegalovirus (CMV), but also in Congenital Zika Syndrome (CZS). The mechanisms by which CMV and ZIKV virus cause these cranial developmental defects have not been elucidated. Inner ear development has been particularly difficult to study, given the inaccessibility and scarcity of the tissue in animal models or on human autopsy; however, it is now possible to culture stem-cell derived otic progenitor cells (OPCs). Here we describe successful in-vitro infection of OPCs with either CMV or ZIKV. We find that ZIKV infection rapidly and strongly induces the expression of type I IFN and inflammatory genes, while simultaneously decreasing otic cell viability in culture that is at least in part attributable to apoptosis. In contrast, CMV infection did not appear to elicit either of these effects and instead demonstrated a clear dysregulation of the expression of many key genes and pathways associated with inner ear development and function, including Cochlin, NGFR, SOX11 and TGF-β signaling. These findings suggest that ZIKV and CMV infections cause congenital hearing loss through very different pathways; that is, by killing progenitor cells in the case of ZIKV infection, and via disruption of critical developmental pathways in the case of CMV infection. In addition to demonstrating differential hCMV and ZIKV pathogenesis mechanisms in OPCs, this study highlights the advantages of otic progenitor cell models for the study of congenital hearing loss induced by viral infection.
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Project description:We show that HCMV infection of human induced pluripotent stem cell (hiPSC)-derived brain organoids can recapitulate severe clinical manifestations such as microcephaly. We demonstrate that infection of hiPSC-derived brain organoids by the “clinical-like” HCMV strain TB40/E results in substantially reduced brain organoid growth, impaired formation of cortical layers, abnormal calcium signaling, and disrupted neural network. Accordingly, RNA-seq analysis revealed that genes down-regulated in TB40/E-infected brain organoids include those involved in neural development and calcium signaling. Moreover, we show that the impeded brain organoid development and abnormal neural network caused by TB40/E infection can be prevented by neutralizing antibodies (NAbs) that recognize different epitopes of the HCMV envelope pentamer complex (PC), a major target of HCMV-specific humoral immunity. These results demonstrate in a three-dimensional human cellular biosystem that HCMV can cause severe brain malformation and disrupt calcium signaling and neural network activity. This study also provides insights into the potential capacity of NAbs to mitigate brain defects resulted from congenital HCMV infection.
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