Pathogenic dengue virus TW2015 strain infection triggers anaerobic glycolysis and enhances mortality in diabetic mice

Dengue virus (DENV) strains with high pathogenicity and transmissibility pose significant public health challenges, especially in tropical and subtropical regions. Underlying conditions such as diabetes mellitus and renal diseases significantly increase the risk of severe dengue. The DENV-2 strain, responsible for a severe outbreak in Taiwan in 2015, exhibits enhanced pathogenicity and transmissibility in a mosquito-mouse transmission model. In this study, we demonstrated that pathogenic DENV infection leads to elevated lactate levels and hypoglycemia in mice, correlating with increased mortality in streptozotocin-induced diabetic models. In infected cells, pathogenic DENV induces rapid eIF2α phosphorylation, extensive ER membrane aggregation, disrupted calcium transfer to mitochondria, and mitochondrial dysfunction, which may contribute to excessive lactate production. Notably, inhibition of lactate production reduced viremia and mortality in mice. These findings highlight the role of metabolic dysregulation in DENV pathogenesis and provide insights into the mechanisms driving severe dengue, particularly in patients with underlying comorbidities. IMPORTANCE DENV is a mosquito-borne virus that can cause severe illness, particularly in tropical and subtropical regions. In 2015, a strain of DENV-2 caused a major outbreak in Taiwan with high mortality rates. People with conditions like diabetes or kidney disease were more likely to develop severe dengue. In our study, we found that this highly pathogenic virus caused mice to have high levels of lactate and low blood sugar before death. In diabetic mice, the virus caused even higher death rates. The virus impairs cellular energy production by disrupting communication between the endoplasmic reticulum and mitochondria, potentially leading to excessive lactate accumulation. Blocking lactate production helped reduce viremia and death rate. These findings suggest that the virus’s impact on metabolism may play a role in severe illness, especially for people with pre-existing health issues.