Hyperglycemia facilitates dengue virus infection and host immune alteration

Abstract

Abstract Patients with diabetes mellitus are highly comorbid with severe dengue diseases caused by the dengue virus (DENV). In search of possible host factors involved in DENV infection under hyperglycemic stress, cells and murine treated with high glucose (HG) increase viral protein expression and virion release but have no effects on antiviral interferon responses as well as viral early infectious stage. Following HG stimulation, a cellular replicon-based assay displays an increased viral translation while the glucose uptake inhibitor phloretin treatment blocks such an effect. Treating HG causes increases in the protein and gene expression of translational factor poly(A)-binding protein (PABP) in a glucose transporter-associated PI3K/AKT-regulated manner. PABP silence further causes a significant decrease in HG-increased virion production. In addition, HG treatment enhances the formation of the PABP-eukaryotic translation initiation factor 4G complex, regulated by protein-disulfide isomerase. Furthermore, streptozotocin-treated hyperglycemic mice reveal increased mortality, brain viral protein expression, and viral loads under DENV infection. This study demonstrates that hyperglycemic stress facilitates DENV infection by strengthening PABP-mediated viral translation. This work is supported by the grants from the National Science and Technology Council (NSTC109-2327-B-006-010 and 110-2320-B-038-064-MY3), Taipei, Taiwan.