Chikungunya virus infection under high glucose environment reverts insulin unresponsiveness and promotes cellular metabolic shift to increase anaplerosis and virion production

Abstract

Aims: Chikungunya virus (CHIKV) is a medically significant arbovirus responsible for Chikungunya fever (CHIKF), a debilitating disease marked by persistent joint and muscle pain. The most severe outcomes of CHIKF, including mortality, are frequently observed in individuals with comorbidities diabetes mellitus (DM). This study aimed to investigate how varying glucose concentrations influence CHIKV infection.

Materials and methods: Human umbilical vein endothelial cells (HUVEC) were cultured in normal glucose (NG - 5.5 mM glucose) or high glucose (HG - 25 mM glucose) to mimic normoglycemia and hyperglycemia conditions. Cells were infected with CHIKV and changes in host glucose metabolism were evaluated. Metabolic flux, viral replication, and cellular insulin sensitivity were assessed through biochemical, molecular analyses and metabolomics.

Key findings: CHIKV infection modulates host cell metabolism in a glucose-dependent manner. Under NG conditions, the virus regulates glucose metabolism to support replication and virion production. In contrast, HG environments enhance viral replication, exploiting the altered metabolic landscape. Notably, CHIKV restores insulin sensitivity in HG conditions, leading to increased glucose uptake. It also promotes anaplerotic reactions by diverting tricarboxylic acid (TCA) cycle intermediates toward amino acid synthesis and upregulates glycolytic flux into the hexosamine biosynthesis pathway (HBP).

Significance: These findings provide mechanistic insight into how hyperglycemia associated with DM can exacerbate CHIKV pathogenesis. The virus's ability to hijack and redirect host metabolic processes in high glucose environments may underline the worsened disease severity observed in diabetic patients. Understanding these interactions could inform targeted therapeutic strategies for managing CHIKF in individuals with metabolic comorbidities.

Keywords: Anaplerosis; Chikungunya fever; Chikungunya virus; Diabetes; Glucose metabolismo; Hyperglycemia.