Molecular alterations in the extracellular matrix in the brains of newborns with congenital Zika syndrome
- 9 June 2020
- journal article
- research article
- Published by American Association for the Advancement of Science (AAAS) in Science Signaling
- Vol. 13 (635)
- https://doi.org/10.1126/scisignal.aay6736
Abstract
Zika virus (ZIKV) infection during pregnancy can cause a set of severe abnormalities in the fetus known as congenital Zika syndrome (CZS). Experiments with animal models and in vitro systems have substantially contributed to our understanding of the pathophysiology of ZIKV infection. Here, to investigate the molecular basis of CZS in humans, we used a systems biology approach to integrate transcriptomic, proteomic, and genomic data from the postmortem brains of neonates with CZS. We observed that collagens were greatly reduced in expression in CZS brains at both the RNA and protein levels and that neonates with CZS had several single-nucleotide polymorphisms in collagen-encoding genes that are associated with osteogenesis imperfecta and arthrogryposis. These findings were validated by immunohistochemistry and comparative analysis of collagen abundance in ZIKV-infected and uninfected samples. In addition, we showed a ZIKV-dependent increase in the expression of cell adhesion factors that are essential for neurite outgrowth and axon guidance, findings that are consistent with the neuronal migration defects observed in CZS. Together, these findings provide insights into the underlying molecular alterations in the ZIKV-infected brain and reveal host genes associated with CZS susceptibility.Funding Information
- Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (88881.130757/2016-01)
- Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (001)
- Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (001)
- Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (001)
- Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (001)
- Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (88887.130697)
- Conselho Nacional de Desenvolvimento Científico e Tecnológico (303170/2017-4)
- Fundação de Amparo à Pesquisa do Estado do Rio de Janeiro (26/202.903/20)
- Conselho Nacional de Desenvolvimento Científico e Tecnológico (313662/2017-7)
- Fundação de Amparo à Pesquisa do Estado de São Paulo (2017/50137-3)
- Fundação de Amparo à Pesquisa do Estado de São Paulo (2012/19278-6)
- Fundação de Amparo à Pesquisa do Estado de São Paulo (2018/14933-2)
- Fundação de Amparo à Pesquisa do Estado de São Paulo (2018/21934-5)
- Fundação de Amparo à Pesquisa do Estado de São Paulo (2013/08216-2)
- Financiadora de Estudos e Projetos (01.16.0078.00)
- Conselho Nacional de Desenvolvimento Científico e Tecnológico (440900/2016-6)
- Fundação de Amparo à Pesquisa do Estado do Rio de Janeiro (E-26/202.650/2018)
- Conselho Nacional de Desenvolvimento Científico e Tecnológico (440613/2016-7)
This publication has 84 references indexed in Scilit:
- STAR: ultrafast universal RNA-seq alignerBioinformatics, 2012
- COL4A1 and COL4A2 mutations and disease: insights into pathogenic mechanisms and potential therapeutic targetsHuman Molecular Genetics, 2012
- Fast gapped-read alignment with Bowtie 2Nature Methods, 2012
- COL4A1 mutations in patients with sporadic late‐onset intracerebral hemorrhageAnnals of Neurology, 2011
- Extracellular matrix and matrix receptors in blood–brain barrier formation and strokeDevelopmental Neurobiology, 2011
- dbNSFP: A lightweight database of human nonsynonymous SNPs and their functional predictionsHuman Mutation, 2011
- A framework for variation discovery and genotyping using next-generation DNA sequencing dataNature Genetics, 2011
- Integrative genomics viewerNature Biotechnology, 2011
- The Genome Analysis Toolkit: A MapReduce framework for analyzing next-generation DNA sequencing dataGenome Research, 2010
- Cytoscape: A Software Environment for Integrated Models of Biomolecular Interaction NetworksGenome Research, 2003