Wednesday, February 5, 2025
2/5/2025
Project Summary/Abstract The 2015-2016 Zika virus (ZIKV) outbreaks in the Americas have become a major global health concern due to their association with pre-natal birth defects such as microcephaly. Since the last outbreak, ZIKV has spilled back to the wildlife to establish persistent reservoir populations, and this has sparked concerns of future sylvatic transmissions that could ignite the next pandemic. Although ZIKV infection during pregnancy has been associated with microcephaly, it is important to note that premature cranial suture fusion (craniosynostosis) has been reported in 88% of babies with severe ZIKV infection and there is an ~22-fold increase in risk of developing craniosynostosis in ZIKV-infected babies compared to genetic occurrence. Aberrant osteogenic activation in the skull suture mesenchyme leads to premature cranial suture fusion, called craniosynostosis. In fact, ~30% of a prospective Brazilian cohort of ZIKV-exposed children showed delayed childhood neurodevelopment and neurosensory alterations. This indicates the craniofacial deformities are linked to severe neurodevelopmental defects. Despite serious health concern, no study has been done for ZIKV-induced craniosynostosis. Our preliminary observations in a 438 Brazilian cohort showed cranial suture fusions in ZIKV- infected infants. Intriguingly, prenatal ZIKV-infection. Using immunocompetent hSTAT2 KI mouse model, we demonstrated that prenatal ZIKV infection resulted in vertical transmission of virus to fetus side, resulting in severe birth defects such as microcephaly, brain calcification and craniosynostosis. Using this in vivo ZIKV mouse model, we have demonstrated significant downregulation of Gli1 expression, while osteogenic differentiation gene expression was significantly increased in sagittal suture tissues of ZIKV-infected mice. Surprisingly, ZIKV expression library screen showed that NS1 was sufficient to induce osteogenic differentiation in cranial osteoprogenitor cells. Based on these preliminary data, we hypothesize that ZIKV infects cranial suture mesenchyme cells to induce osteogenic differentiation of GLI1+ cells and craniosynostosis. Herein, I seek to address the following questions: (i) which host suture cell types are targeted for ZIKV-induced craniofacial suture fusion in vivo, (ii) characterize the host transcriptomic landscape of ZIKV-infected calvaria suture microenvironment, and (iii) which and how ZIKV proteins triggers craniofacial suture fusion upon infection. This proposal is highly innovative and translational, and potentially shed new insights to congenital ZIKV-induced fetal cranial suture anomalies.
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