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Molecular Alterations of Extracellular Matrix in the Brain of Newborns with Congenital Zika Syndrome

ABSTRACT: Zika virus (ZIKV) infection during pregnancy could cause a set of severe abnormalities in the fetus known as congenital Zika syndrome (CZS). Experiments using animal models and in vitro systems significantly contributed to our understanding of the physiopathology of ZIKV infection. However, the molecular basis of CZS is not yet studied in humans. Here, we used a systems biology approach to integrate transcriptomic, proteomic and genomic data from post-mortem brains of neonates with CZS. We observed that collagen genes were greatly reduced in CZS brains at both the RNA and protein levels and that neonates with CZS have several polymorphisms in collagen genes associated with osteogenesis imperfect and arthrogryposis. These findings were validated using immunohistochemistry and collagen staining of ZIKV infected and non-infected samples. Additionally, it was found that cell adhesion genes that are essential for neurite outgrowth and axon guidance were up-regulated and thereby confirmed the neuronal migration defects observed. This work provided new insights into the underlying mechanisms of CZS and revealed host genes associated with CZS susceptibility.

ORGANISM(S): Homo sapiens

PROVIDER: GSE125554 | GEO | 2020/05/18

REPOSITORIES: GEO

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Project description:During pregnancy, the Zika virus (ZIKV) can be vertically transmitted, causing Congenital Zika Syndrome (CZS) in fetuses. ZIKV infection in early gestational trimesters increases the chances to develop CZS. This syndrome involves several pathologies with a difficult diagnosis, which usually occurs in the postnatal stage. In this work, we aim to identify biological processes and molecular pathways related to CZS development and propose a series of putative protein and metabolite biomarkers for CZS prognosis in early pregnancy trimesters. Twenty-five serum samples of pregnant women were analyzed. For biological analysis, samples were separated into 3 biological groups composed of a control group of healthy pregnant women and two groups of ZIKV-infected pregnant women bearing non- microcephalic and microcephalic fetuses. Control and ZIKV-infected groups - without microcephalic fetuses - were subdivided into healthy and Cognitive Developmental Delay (CDD) newborns for biomarker analysis. We detected over 1,000 proteins and 500 metabolites by bottom-up proteomics and untargeted metabolomics, respectively. Statistical approaches - (t-Student, Limma, ANOVA, and DIABLO) - were applied to find CZS differentially abundant proteins (DAP) and metabolites (DAM). Enrichment analysis (i.e., biological processes and molecular pathways) of the DAP and the DAM allowed us to identify the ECM organization and proteoglycans, amino acid metabolism, and arachidonic acid metabolism as signatures in the CZS development. Five proteins and four metabolites were selected as CZS biomarkers candidates. The protein-based model indicated superior performance values for the Vitamin K-dependent protein S, Selenoprotein P, Inter-alpha- trypsin inhibitor heavy chain H2, Kallistatin, and Protein Z-dependent protease inhibitor proteins. Furthermore, the metabolite-based model was able to predict CZS with a probability of 90%. Serum multi-omics analysis led us to propose for further studies nine potential biomarkers for CZS early prognosis with high sensitivity and specificity.

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Molecular Alterations of Extracellular Matrix in the Brain of Newborns with Congenital Zika Syndrome

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