Evaluation of miRNAs role in the immunopathogenesis of Microcephaly caused by ZIKV in experimental models

Abstract

Abstract Viral infections have always been the cause of serious human diseases, usually increasing rates of morbidity and mortality worldwide. In 2015, the flavivirus Zika virus (ZIKV) caused an alarming increase in the number of babies born with microcephaly. Genetic differences, mainly related to immune response, are known to influence susceptibility to infection, once is very important in blocking viral replication and may be modulated by several different factors, in which, miRNAs play a key role. Still very little is known about the involvement of miRNAs during ZIKV infection. In this context, we evaluated the role of miRNAs during ZIKV experimental infection. We performed miRNAs analysis in vitro using CNS cells and, in vivo, with SJL animals susceptible to infection. Analyzing human neurons, we observed that ZIKV was able to reduce miR-9 and this reduction is known to cause cerebral cortex thickness reduction and ventriculomegaly, characteristics similar to microcephaly. In human neuronal precursor cells, ZIKV was able to reduce miR-194, miR-302b and miR-302c expression and consequently increased MXD1, a transcriptional repressor. On the other hand, ZIKV infection increased miR-295 and miR-302d expression leading to a reduction of AHR repressor and molecules involved in neurodevelopment, neuroD4, and neuroD6. In SJL fetal brain a miR-146 increase leading a decrease of IRAK1, favoring viral replication. Taken together, these data are indicative that ZIKV is able to modulate miRNA profile to regulate important molecules involved in neurodevelopment and antiviral immune response, evidencing the importance of these regulatory molecules, which may help us to better understand immunopathogenic mechanisms of microcephaly caused by ZIKV