Elucidation of the Roles of Mitochondrial Dysfunction and Metabolic Alteration in Viral Pathogenesis

Infectivity and virulence of pathogens are affected by host’s microenvironment. Our previous studies have shown that redox status affects viral pathogenesis. Enteroviral infection itself can lead to mitochondrial dysfunction and generation of reactive oxygen species (ROS), which in turn enhances enteroviral replication and cytopathic effect. Interruption of such vicious cycle through suppression of mitochondrial ROS generation leads to inhibition of viral replication. Mitochondrial dysfunction may play important roles in enteroviral pathogenesis. Mitochondria lie at the central hub of cellular metabolism, redox homeostasis, energy production and antiviral signaling. As mitochondria are sites for numerous biochemical reactions, and can regulate cellular redox status through various NADPH-generating systems, viral infection leads to hijacking of mitochondrial functions to meet the needs of viral replication. The inter-relationship between mitochondria, metabolism, redox homeostasis and viral pathogenesis is not completely understood. One of the aims of the present proposal is to apply metabolomics approach to study how enteroviral infection affects global metabolism of host cells. Functional approach will be taken to elucidate the roles of specific metabolic changes in viral pathogenesis. Additionally, we will study the fluxes of metabolic pathways specifically targeted by enterovirus. Moreover, the mechanism underlying enterovirus-induced mitochondrial dysfunction and ROS generation remains elusive. Our preliminary studies have recently shown that exogenous expression of specific enteroviral proteins induces ROS generation. We will study how enteroviral proteins interact with host proteins to affect mitochondrial functions, and to induce metabolic changes and redox imbalance. To gain an in-depth understanding of the relationship between mitochondria and enteroviral pathogenesis, we will apply a functional approach to experimentally alter the state and functions of mitochondria, and will study the subsequent effects on metabolism, redox balance and correlative change in viral susceptibility. Furthermore, using a newly developed animal model of enteroviral infection, we will correlate the changes in pathology, metabolism and mitochondrial physiology of affected tissues. The effect of nutritional supplementation or deprivation of metabolites (or their precursors) on metabolism and viral pathogenesis of infected animal will be examined. The in vitro and in vivo findings help us to understand the roles of mitochondria and metabolism in viral pathogenic mechanism. Through the present study, we will gain a better understanding of the roles of mitochondria, and host’s metabolic and redox status in host-virus interactions. In the era of preventive medicine, this project will open an avenue to prevention and therapy of viral infection.

Project ID:PC10501-1877
External Project ID:MOST104-2320-B182-022-MY3