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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.

SUBMITTER: Shen TJ

PROVIDER: S-EPMC9675471 | biostudies-literature | 2022 Nov

REPOSITORIES: biostudies-literature

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

Shen Ting-Jing TJ Chen Chia-Ling CL Tsai Tsung-Ting TT Jhan Ming-Kai MK Bai Chyi-Huey CH Yen Yu-Chun YC Tsai Ching-Wen CW Tseng Po-Chun PC Yu Chia-Yi CY Lin Chiou-Feng CF

JCI insight 20221108 21

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-transfect ...[more]

PMID: 36125898

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Project description:BACKGROUND:The incidence of dengue is rising steadily in Malaysia since the first major outbreak in 1973. Despite aggressive measures taken by the relevant authorities, Malaysia is still facing worsening dengue crisis over the past few years. There is an urgent need to evaluate dengue cases for better understanding of clinic-laboratory spectrum in order to combat this disease. METHODS:A retrospective analysis of dengue patients admitted to a tertiary care teaching hospital during the period of six years (2008 - 2013) was performed. Patient's demographics, clinical and laboratory findings were recorded via structured data collection form. Patients were categorized into dengue fever (DF) and dengue hemorrhagic fever (DHF). Appropriate statistical methods were used to compare these two groups in order to determine difference in clinico-laboratory characteristics and to identify independent risk factors of DHF. RESULTS:A total 667 dengue patients (30.69?±?16.13 years; Male: 56.7 %) were reviewed. Typical manifestations of dengue like fever, myalgia, arthralgia, headache, vomiting, abdominal pain and skin rash were observed in more than 40 % patients. DHF was observed in 79 (11.8 %) cases. Skin rash, dehydration, shortness of breath, pleural effusion and thick gall bladder were more significantly (P?<?0.05) associated with DHF than DF. Multivariate regression analysis demonstrated presence of age?>?40 years (OR: 4.1, P?<?0.001), secondary infection (OR: 2.7, P?=?0.042), diabetes mellitus (OR: 2.8, P?=?0.041), lethargy (OR: 3.1, P?=?0.005), thick gallbladder (OR: 1.7, P?=?0.029) and delayed hospitalization (OR: 2.3, P?=?0.037) as independent predictors of DHF. Overall mortality was 1.2 % in our study. CONCLUSIONS:Current study demonstrated that DF and DHF present significantly different clinico-laboratory profile. Older age, secondary infection, diabetes mellitus, lethargy, thick gallbladder and delayed hospitalization significantly predict DHF. Prior knowledge of expected clinical profile and predictors of DHF/DSS development would provide information to identify individuals at higher risk and on the other hand, give sufficient time to clinicians for reducing dengue related morbidity and mortality.

Dataset Information

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

Publications

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

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