Abstract
Zika virus (ZIKV) is an emerging mosquito-borne flavivirus that has attracted global attention and international awareness. ZIKV infection exhibits mild symptoms including fever and pains; however, ZIKV has recently been shown to be related to increased birth defects, including microcephaly, in infants. In addition, ZIKV is related to the onset of neurological disorders, such as a type of paralysis similar to Guillain-Barré syndrome. However, the mechanisms through which ZIKV affect neuronal cells and myeloid dendritic cells and how ZIKV avoids host immunity are unclear. Accordingly, in this study, we analyzed RNA sequencing data from ZIKV-infected neuronal cells and myeloid dendritic cells by comparative network analyses using protein-protein interaction information. Comparative network analysis revealed major genes showing differential changes in the peripheral neurons, neural crest cells, and myeloid dendritic cells after ZIKV infection. The genes were related to DNA repair systems and prolactin signaling as well as the interferon signaling, neuroinflammation, and cell cycle pathways. These pathways were interconnected by the interaction of proteins in the pathway and significantly regulated by ZIKV infection in neuronal cells and myeloid dendritic cells. Our analysis showed that neuronal cell damage occurred through up-regulation of neuroinflammation and down-regulation of the DNA repair system, but not in myeloid dendritic cells. Interestingly, immune escape by ZIKV infection could be caused by downregulation of prolactin signaling including IRS2, PIK3C3, JAK3, STAT3, and IRF1 as well as mitochondria dysfunction and oxidative phosphorylation in myeloid dendritic cells. These findings provide insight into the mechanisms of ZIKV infection in the host and the association of ZIKV with neurological and immunological symptoms, which may facilitate the development of therapeutic agents and vaccines.
Highlights
Zika virus (ZIKV) disease is an epidemic caused by ZIKV, an icosahedral enveloped arbovirus with a positive-sense, single-stranded RNA genome of approximately 11 kb
Based on the criteria of log2 greater than 1 and false discovery rate of less than 0.05, 1171 genes were found to be differentially expressed in ZIKV-infected human peripheral neurons (hPNs) (604 upregulated genes and 567 downregulated genes), 1672 genes were differentially expressed in ZIKVinfected human neural crest cells (hNCCs) (887 upregulated genes and 785 downregulated genes), and 2601 genes were differentially expressed in ZIKV-infected myeloid dendritic cells (mDCs) (1239 upregulated genes and 1362 downregulated genes)
We investigated the expression of ZIKV-induced genes in neurons, as the primary target cells of ZIKV infection and main cause of neuronal cell death
Summary
Zika virus (ZIKV) disease is an epidemic caused by ZIKV, an icosahedral enveloped arbovirus with a positive-sense, single-stranded RNA genome of approximately 11 kb. ZIKV belongs to the genus Flavivirus and family flaviviridae, which includes dengue virus, yellow fever virus, and West Nile virus [1]. ZIKV is transmitted to humans mainly through the bite of infected Aedes aegypti and Aedes albopictus (Asian tiger mosquito). ZIKV-infected men can transmit the virus to their sexual partners [2]. ZIKV strains are grouped into two major lineages, African and Asian, as confirmed by phylogenetic analyses [3]. Recent studies showed that the Asian lineage of ZIKV is strongly associated with microcephaly and Guillain-Barresyndrome [4,5]. The marked increase in neonates born with microcephaly in northeast Brazil was shown to be caused by intrauterine exposure to ZIKV [6]
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