Project description:Zika virus (ZIKV), a pathogen of global health concern, is transmitted to humans by Aedes mosquitoes. However, the molecular interactions between the vector and the virus remain largely unexplored. We demonstrated that ZIKV and dengue virus (DENV) have similar tropism and infection kinetics in two mosquito strains with different degrees of susceptibility to infection. Comparison of Aedes aegypti’s molecular responses to ZIKV and DENV infection indicated that around 40% of the mosquito’s infection-responsive transcriptome is virus-specific. Regulated genes also included key factors of the mosquito’s anti-viral immunity, pointing to the possible involvement of the Toll innate immune pathway. Comparison of ZIKV and DENV infection-responsive transcriptome data to those for yellow fever virus and West Nile virus identified 26 genes likely to play key roles in virus infection of Aedes mosquitoes. Through reverse genetic analyses, we showed that the Toll and the Jak/Stat innate immune pathways mediate increased resistance to ZIKV infection, and the virus use vATPase and inosine-5’-monophosphate dehydrogenase as mosquito’s host factors.
Project description:Administration of recombinant interferons to 3D brain organoid cultures infected with ZIKV identifies IFN-beta as compound that alleviates organoid damage and inhibits ZIKV
Project description:Dendritic cells are key targets for ZIKV infection. To identify host pathways manipulated by ZIKV in dendritic cells, we developed a system that enables characterization of genome-wide transcriptional and epigenetic changes in ZIKV-infected and neighboring, uninfected primary human dendritic cells.
Project description:We employed 3D brain organoids generated from induced human pluripotent stem cells (ihPSC) as ex vivo model of viral infection in the developing brain and utilized wild type (WT) ZIKV producing sfRNA and mutant ZIKV deficient in production of sfRNA. Global transcriptome profiling by RNA-Seq revealed that production of sfRNA affects expression of >1000 genes. We uncovered that in addition to activation of pro-apoptotic pathways, organoids infected with sfRNA-producing WT, but not sfRNA-deficient mutant ZIKV, exhibited strong down-regulation of genes involved in signaling pathways that control neuron differentiation and brain develop-ment, which indicates the requirement of sfRNA for suppression of neurodevelopment associated with ZIKV infection. Using gene set enrichment analysis and gene network reconstruction, we demonstrated that the effect of sfRNA on pathways that control brain development occurs via crosstalk between Wnt-signaling and proapoptotic pathways.
Project description:Zika virus (ZIKV) is a mosquito-transmitted positive-sense RNA virus in the family Flaviviridae. ZIKV infections are associated with neurodevelopmental deficiencies termed Congenital Zika Syndrome. ZIKV strains are grouped into three phylogenetic lineages: East African, West African, and Asian, which contains the American lineage. RNA virus genomes exist as genetically-related sequences. The heterogeneity of these viral populations is implicated in viral fitness, and genome diversity is correlated to virulence. This study examines genetic diversity of representative ZIKV strains from all lineages utilizing next generation sequencing (NGS). Inter-lineage diversity results indicate that ZIKV lineages differ broadly from each other; however, intra-lineage comparisons of American ZIKV strains isolated from human serum or placenta show differences in diversity when compared to ZIKVs from Asia and West Africa. This study describes the first comprehensive NGS analysis of all ZIKV lineages and posits that sub-consensus-level diversity may provide a framework for understanding ZIKV fitness during infection.
Project description:We report that ZIKV noncoding RNA (sfRNA) affect expression of mosquito genes upon ZIKV infection. We constructed sfRNA-deficient ZIKV mutant (xrRNA2') and conducted transcriptome-wide gene expression profiling of mosquitos infected with WT and xrRNA2' viruses. We found that sfRNA inhibits apoptosis in the infected tissues of Ae. aegypti by altering expression of mosquito genes that control cell death and survival.
Project description:Zika Virus (ZIKV) induces ocular complications in infants born from ZIKV infected mothers during pregnancy. We previously reported that ZIKV is permeable to cells lining the blood-retinal barrier. In this study, we measure the alteration of host transcriptome by ZIKV using primary retinal pigmented epithelial (RPE) cells.
