Unveiling The Role Of Antibody-Dependent Enhancement In The Identification Of Potential Therapeutic Drugs For Dengue Management Following Zika Infection: A Bioinformatics Analysis
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Abstract
Introduction: Global warming is expanding geographical range suitable for mosquito reproduction, leading to an increased incidence of arboviral infections, including dengue (DENV) and Zika virus (ZIKV). These virus exhibit structural similarities, developing antibody-dependent enhancement (ADE) in DENV following ZIKV infection. Therefore, it is critical to understand the underlying mechanisms of ADE and find potential therapeutic drugs.
Objective: This bioinformatics analysis aimed to identify key genes and find potential therapeutic drugs of DENV following ZIKV infection.
Method: Two independent datasets from B-cells of ZIKV-infected and plasmablast of DENV-infected patients were analysed. Differentially expressed genes (DEGs) were identified and compared between the two groups. Gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and STRING databases were used to explore the functions of these genes. The search for drugs capable of reversing important gene expression changes was carried out using Library of Integrated Network-Based Cellular Signatures (LINCS) L1000 database.
Result and Discussion: DEGs analyses revealed that 28 genes were upregulated in DENV and downregulated in ZIKV, and 30 genes vice versa. Enrichment analysis of the former DEGs highlighted HLA-DRB1, HLA-DRB5, and HLA-DPA1 genes as significant modulators of the immune response. Protein-protein interaction (PPI) network further proved strong connectivity between these three genes. Vorinostat and trichostatin-a were identified as potential drugs to reduce ZIKV antibody production, without compromising immune response to DENV.
Conclusion: This study successfully identified the HLA-DRB1 and HLA-DPA1 genes as potential targets for existing drugs that could mitigate the severity of the ADE phenomenon. Additionally, a list of existing drugs that could potentially be repurposed to combat ADE has been compiled. Further in vitro and in vivo studies, as well as clinical trials, will be essential to confirm our findings and the optimal timing for drug administration.
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