Molecular alterations in the extracellular matrix in the brains of newborns with congenital Zika syndrome
Renato Santana Aguiar, Fabio Baldivia Pohl, Guilherme Loss de Morais, Fábio César Sousa Nogueira, Joseane Biso de Carvalho, Letícia da Cunha Guida, Luis Willian Pacheco Arge, Adriana Melo, Maria Elizabeth Lopes Moreira, Daniela P. Cunha, Leonardo Henrique Ferreira Gomes, Elyzabeth Avvad Portari, Erika Velásquez, Rafael D. Melani, Paula Pezzuto, Fernanda Luz de Castro, Victor Emmanuel Viana Geddes, Alexandra Lehmkuhl Gerber, Girlene Souza de Azevedo, Bruno Luiz Fonseca Schamber‐Reis, Alessandro L. Gonçalves, Inácio L.M. Junqueira-de-Azevedo, Milton Yutaka Nishiyama, Paulo Lee Ho, Alessandra Soares‐Schanoski, Viviane Schuch, Amílcar Tanuri, Leila Chimelli, Zilton Vasconcelos, Gilberto B. Domont, Ana Tereza Ribeiro de Vasconcelos, Helder I. Nakaya
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.