Congenital Zika syndrome is associated with maternal protein malnutrition

Abstract

MRC Zika Rapid Response Grant (MC_PC_15102), FAPERJ (E_03/2017E_03/2017), the Brazilian Ministry of Health (DSAST/SVS 25380.001612/2017-70), and the AAPA Professional Development GrantFederal University of Rio de Janeiro. Institute of Biomedical Sciences. Rio de Janeiro, RJ, Brazil / Institute for Studies in Neuroscience and Complex Systems. Buenos Aires, Argentina.Federal University of Rio de Janeiro. Institute of Biology. Department of Genetics. Rio de Janeiro, RJ, Brazil.Federal University of Rio de Janeiro. Institute of Biology. Department of Genetics. Rio de Janeiro, RJ, Brazil.Federal University of Rio de Janeiro. Microbiology Institute Paulo de Góes. Rio de Janeiro, RJ, Brazil.Federal University of Pará. Biological Science Institute. Belém, PA, Brazil.Federal University of Rio de Janeiro. Nuclear Instrumentation Laboratory. Rio de Janeiro RJ, Brazil.Federal University of Rio de Janeiro. Institute of Biomedical Sciences. Rio de Janeiro, RJ, Brazil.Federal University of Rio de Janeiro. Institute of Biomedical Sciences. Rio de Janeiro, RJ, Brazil.Federal University of Rio de Janeiro. Microbiology Institute Paulo de Góes. Rio de Janeiro, RJ, Brazil.Federal University of Rio de Janeiro. Institute of Biology. Department of Genetics. Rio de Janeiro, RJ, Brazil.National Center of Structural Biology and Bioimaging. Rio de Janeiro, RJ, Brazil.Ministério da Saúde. Secretaria de Vigilância em Saúde. Instituto Evandro Chagas. Centro de Inovações tecnológicas. Ananindeua, PA, Brasil.Ministério da Saúde. Secretaria de Vigilância em Saúde. Instituto Evandro Chagas. Centro de Inovações tecnológicas. Ananindeua, PA, Brasil.State Institute of Brain Paulo Niemeyer. Rio de Janeiro, RJ, Brazil.Federal University of Rio de Janeiro. Institute of Biology. Department of Genetics. Rio de Janeiro, RJ, Brazil.Institute for Studies in Neuroscience and Complex Systems. Buenos Aires, Argentina.Fundação Oswaldo Cruz. Oswaldo Cruz Institute. Rio de Janeiro, RJ, Brazil.Harvard T. H. Chan School of Public Health. Department of Global Health and Population. Boston, MA, USA.Zika virus (ZIKV) infection during pregnancy is associated with a spectrum of developmental impairments known as congenital Zika syndrome (CZS). The prevalence of this syndrome varies across ZIKV endemic regions, suggesting that its occurrence could depend on cofactors. Here, we evaluate the relevance of protein malnutrition for the emergence of CZS. Epidemiological data from the ZIKV outbreak in the Americas suggest a relationship between undernutrition and cases of microcephaly. To experimentally examine this relationship, we use immunocompetent pregnant mice, which were subjected to protein malnutrition and infected with a Brazilian ZIKV strain. We found that the combination of protein restriction and ZIKV infection leads to severe alterations of placental structure and embryonic body growth, with offspring displaying a reduction in neurogenesis and postnatal brain size. RNA-seq analysis reveals gene expression deregulation required for brain development in infected low-protein progeny. These results suggest that maternal protein malnutrition increases susceptibility to CZS