Hyperglycemia exacerbates dengue virus infection by facilitating poly(A)-binding protein–mediated viral translation
Ting-Jing Shen, Chia-Ling Chen, Tsung-Ting Tsai, Ming-Kai Jhan, Chyi-Huey Bai, Yu-Chun Yen, Ching-Wen Tsai, Po-Chun Tseng, Chia-Yi Yu, Chiou-Feng Lin
Ting-Jing Shen, Chia-Ling Chen, Tsung-Ting Tsai, Ming-Kai Jhan, Chyi-Huey Bai, Yu-Chun Yen, Ching-Wen Tsai, Po-Chun Tseng, Chia-Yi Yu, Chiou-Feng Lin
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Research Article Infectious disease Virology

Hyperglycemia exacerbates dengue virus infection by facilitating poly(A)-binding protein–mediated viral translation

Abstract

Diabetes mellitus (DM) is highly comorbid with severe dengue diseases; however, the underlying mechanisms are unclear. Patients with DM have a 1.61-fold increased risk of developing dengue hemorrhagic fever. In search of host factors involved in dengue virus (DENV) infection, we used high-glucose (HG) treatment and showed that HG increased viral protein expression and virion release but had no effects on the early stages of viral infection. After HG stimulation, DENV–firefly luciferase–transfected assay and cellular replicon–based assay indicated increased viral translation, whereas using the glucose uptake inhibitor phloretin blocked this effect. HG treatment increased the translational factor poly(A)-binding protein (PABP) in a glucose transporter–associated, PI3K/AKT-regulated manner. Silencing PABP significantly decreased HG-prompted virion production. HG enhanced the formation of the PABP–eukaryotic translation initiation factor 4G complex, which is regulated by protein–disulfide isomerase. Hyperglycemia increased PABP expression, mortality rate, viral protein expression, and viral loads in streptozotocin-induced DM mice. Overall, hyperglycemic stress facilitates DENV infection by strengthening PABP-mediated viral translation.

Authors

Ting-Jing Shen, Chia-Ling Chen, Tsung-Ting Tsai, Ming-Kai Jhan, Chyi-Huey Bai, Yu-Chun Yen, Ching-Wen Tsai, Po-Chun Tseng, Chia-Yi Yu, Chiou-Feng Lin

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Figure 4

PI3K/AKT signaling contributes to HG-induced PABP expression, which promotes DENV infection.

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PI3K/AKT signaling contributes to HG-induced PABP expression, which prom...
(A) Western blot showed the expression of PABP, NF90, hnRNP, eEF1A, PTB, YB-1, and β-actin in 5.5 or 25 mM glucose (Glu) medium–treated BHK-21 cells for 48 hours. (B) Furthermore, the time course expression of PABP protein also is shown. (C) Western blot showed PABP protein expression in BHK-21 cells that were pretreated with or without PI3K inhibitor (LY294002), the mTOR inhibitor rapamycin (Rapa), or AKT inhibitor (AKTi) for 1 hour followed by 5.5 or 25 mM Glu-containing–medium treatment for 48 hours. (D) Real-time qPCR assays showed the expression of PABP mRNA in 5.5 or 25 mM Glu-treated BHK-21 cells that were pretreated with or without LY294002 and an AKTi for 1 hour and subsequently maintained in medium containing 5.5 or 25 mM Glu for 48 hours. (E) Western blot showed PABP protein expression in BHK-21 cells pretreated with PABP siRNA (siPABP) for 48 hours, followed by incubation with medium containing 25 mM Glu. Cells without control siRNA pretreatment were used as negative control. (F) Plaque assays were conducted to determine the viral titer of BHK-21 cells that were pretreated with PABP siRNA for 48 hours and then infected with DENV 2 (MOI, 1) for an additional 48 hours in 5.5 or 25 mM Glu-containing medium. DMSO was used as a control. The mean ± SD of quantitative data from at least 3 independent experiments are reported. **P < 0.01, ***P < 0.001. RQ, relative quantification.