Abstract Summary/Description
Neurotropic flaviviruses continue to spread and cause human disease in new areas of the world. Powassan virus (POWV) causes encephalitis, including fatal neuroinvasive disease in approximately 10% of cases, and long-lasting neurological sequelae in 50% of survivors. Zika virus (ZIKV) infections have caused a wide spectrum of neurological diseases, such as Guillain-Barré syndrome, myelitis, meningoencephalitis, and congenital microcephaly. MicroRNAs (miRNAs) are a group of small RNAs involved in the regulation of a wide variety of cellular and physiological processes. To identify differentially expressed miRNAs associated with POWV and ZIKV infections, we employed nCounter® Technology (NanoString) to analyze global miRNAs expression in mice brains and primary mouse cortical neurons. Our data demonstrate that POWV and ZIKV infections cause global downregulation of miRNAs with only few up-regulated miRNAs. ZIKV infection also results in downregulation of miRNA processing enzymes including Dicer-1, Drosha, DGCR8, AGO1 and AGO2 in neurons. Biofunctional analysis revealed that POWV- and ZIKV-modulated miRNAs regulate the pathways related to neurological development and neuroinflammatory responses. Moreover, functional studies targeting specific miRNA revealed a critical role of miR-155 in the pathogenesis of POWV and ZIKV infection. Primary mouse cells lacking miR-155 were more susceptible to infection with POWV and ZIKV compared to cells derived from the wild-type mice. Collectively, these data indicate that cellular miRNAs may play a critical role in the pathogenesis of neurotropic flavivirus infection.
