Zika virus targets the human thymic epithelium.

Previous work showed that the thymus can be infected by RNA viruses as HIV and HTLV-1. We thus hypothesized that the thymus might also be infected by the Zika virus (ZIKV). Herein we provide compelling evidence that ZIKV targets human thymic epithelial cells (TEC) in vivo and in vitro. ZIKV-infection enhances keratinization of TEC, with a decrease in proliferation and increase in cell death. Moreover, ZIKV modulates a high amount of coding RNAs with upregulation of genes related to cell adhesion and migration, as well as non-coding genes including miRNAs, circRNAs and lncRNAs. Moreover, we observed enhanced attachment of lymphoblastic T-cells to infected TEC, as well as virus transfer to those cells. Lastly, alterations in thymuses from babies congenitally infected were seen, with the presence of viral envelope protein in TEC. Taken together, our data reveals that the thymus, particularly the thymic epithelium, is a target for the ZIKV with changes in the expression of molecules that are relevant for interactions with developing thymocytes.

Molecular alterations in the extracellular matrix in the brains of newborns with congenital Zika syndrome.

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.

Molecular alterations in the extracellular matrix in the brains of newborns with congenital Zika syndrome

A infecção pelo vírus zika (ZIKV) durante a gravidez pode causar um conjunto de anormalidades graves no feto, conhecidas como síndrome congênita do zika (CZS). Experimentos com modelos animais e sistemas in vitro contribuíram substancialmente para a nossa compreensão da fisiopatologia da infecção pelo ZIKV. Aqui, para investigar a base molecular da CZS em humanos, usamos uma abordagem de biologia de sistemas para integrar dados transcriptômicos, proteômicos e genômicos dos cérebros post-mortem de neonatos com CZS. Observamos que os colágenos foram bastante reduzidos em expressão nos cérebros de CZS nos níveis de RNA e de proteínas e que os neonatos com CZS tinham vários polimorfismos de nucleotídeo único em genes que codificam colágeno que estão associados à osteogênese imperfeita e à artrogripose. Esses achados foram validados por imuno-histoquímica e análise comparativa da abundância de colágeno em amostras infectadas e não infectadas por ZIKV. Além disso, mostramos um aumento dependente de ZIKV na expressão de fatores de adesão celular que são essenciais para o crescimento de neurites e a orientação do axônio, achados consistentes com os defeitos de migração neuronal observados na CZS. Juntos, esses achados fornecem informações sobre as alterações moleculares subjacentes no cérebro infectado pelo ZIKV e revelam genes hospedeiros associados à suscetibilidade à CZS.