Research Summary

Role of mitochondrial dynamics in Dengue virus life cycle and disease pathogenesis

With the lack of effective vaccine or therapy Dengue virus (DENV) is emerging as global health burden. There is an urgent need to unravel the molecular mechanisms underlying the pathophysiology of DENV disease to assist in development of effective therapeutic strategies. Mitochondrial dynamics is an integral cellular process with implications in cellular and mitochondrial homeostasis, metabolism, inflammation, and innate immunity. Viruses may exploit mitochondrial dynamics to facilitate viral infection, evade innate immunity, and as a consequence trigger viral disease pathogenesis. I hypothesize that mitochondrial dynamics plays a critical role in DENV infection and pathogenesis. To elucidate this hypothesis, I will explore the effect of DENV on mitochondrial dynamics and characterize the underlying mechanisms. I will determine if DENV exploits mitochondrial dynamics and mitophagy to benefit the infectious process. Subsequently I will characterize if DENV utilizes the altered mitochondrial dynamics and mitophagy to cripple cellular innate immune signaling. Antibody-dependent enhancement (ADE) of secondary DENV infection is implicated in the exponential increase in inflammatory signaling that lead to lethal dengue disease. I will explore if the ADE promotes defect in mitochondrial quality control thereby causing an accumulation of damaged mitochondria, a major source of mtDNA and mtROS that can trigger inflammasome activation.

Figure Legend: A schematic representation of cellular mitochondrial dynamics during Dengue infection. Physiological perturbations during infection such as endoplasmic reticulum (ER) stress, oxidative stress, and deregulated Ca2+ homeostasis promote mitochondrial injury. Subsequently damaged mitochondria undergo fragmentation to segregate the unhealthy pool which are eliminated by mitophagy (mitochondria-selective autophagy). Together mitochondrial dynamics and mitophagy control mitochondria quality. DENV proteins may also directly promote mitochondrial injury and fragmentation. Damaged and fragmented mitochondria are impaired in innate immune signaling. Defect in mitochondrial quality control promotes the intracellular accumulation of mt-ROS and mt-DNA fragments that can potentiate inflammasome activation.