The Roles of Virus-host Interactions in the Pathogenesis of Dengue and Zika Viral Infections

Download or read book The Roles of Virus-host Interactions in the Pathogenesis of Dengue and Zika Viral Infections written by Makeda Lucretia Robinson and published by . This book was released on 2020 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt: Dengue virus (DENV) and Zika virus (ZIKV) infections are threats to global health. However, the viral and host determinants underlying disease pathogenesis are incompletely understood. To study the host immune responses to dengue infection we aimed to elucidate mechanisms of disease pathogenesis and identify biomarkers predictive of severe dengue (SD). To capture tissue heterogeneity, we developed a single-cell transcriptomic platform that quantifies viral RNA abundance and the host transcriptome in thousands of single cells, and used it to monitor the host response to natural infection in adults' PBMC samples from a Colombia dengue cohort that we established. We showed large heterogeneity in the host response to dengue in a cell subtype specific manner. We discovered that naïve B cells are the predominant cell type associated with viral RNA and that their interferon response genes are upregulated relative to bystander or control uninfected cells. We revealed cell-type specific alterations in gene expression levels prior to progression to SD, such as upregulation of MX2 in naïve B cells and CD163 in CD14+CD16+ monocytes. In parallel, to capture real-world heterogeneity, we used a multi-cohort analysis framework that integrates heterogeneous datasets to identify robust host gene signatures that are generalizable across cohorts, and discovered a 20-gene set predictive of SD using publicly available dengue datasets. The prognostic power of this gene set to distinguish uncomplicated from SD early in the course of illness was validated in silico and prospectively in our dengue cohort. Another flavivirus infection associated with significant morbidity whose pathogenesis is poorly understood is ZIKV. The recent ZIKV epidemic has been associated with microcephaly in neonates as well as Guillain-Barre syndrome and encephalitis in adults. ZIKV infection causes cell death in neuro-progenitor cells, and increased expression of p53, a major regulator of cell death. Here, we evaluated the role of the ZIKV protease (NS2B3) in activating the p53 apoptotic pathway. Our studies showed that NS2B3 alone can trigger apoptosis and identified several novel NSB23 binding partners, including MDM4, an inhibitor of the transregulatory functions of p53, which is a candidate substrate of the protease activity, and two E3 ubiquitin ligases COP1 and CARP2, which lead to p53 degradation by the proteasome. Our data suggests that NS2B3 may inhibit the function of p53 regulatory proteins thereby increasing its protein expression and upregulating p53 target gene transcription leading to apoptosis. Together, these studies have shed light on the roles of virus-host interactions in the pathogenesis of flaviviral infections and provide potential translational avenues for targeted diagnostic and therapeutic interventions for these globally important viruses.