The Roles of Host’s Redox Homeostasis in Viral Pathogenesis

Changes in host’s microenvironment influence the infectivity as well as virulence of pathogens. It is well known that redox homeostasis plays significant roles in normal physiological functions and pathological changes associated with degenerative diseases. Nonetheless, the role of oxidative stress as a host factor of viral infection remains elusive. Using enterovirus 71 (EV71) as model, we demonstrated that oxidative stress enhances viral replication and cytopathic effects in infected cells, which in turn leads to increased production of reactive oxygen species (ROS). It is postulated that EV71 infection initiates a cycle of ROS generation and viral replication. It follows that redox homeostasis in host plays important roles in its interactions with virus, and thus viral pathogenesis. One of the aims of this proposal is to delineate the mechanism underlying the cycle of ROS generation and viral replication. Our preliminary study has shown that the virus-induced oxidative stress was accompanied by changes in mitochondrial morphology and functions. Exogenous expression of individual viral proteins led to ROS generation. It is hypothesized that EV71 viral proteins and host proteins, in particular the mitochondrial ones, interact to induce mitochondrial dysfunction and ROS formation. Proteomic approaches will be taken to identify cellular proteins that interact with viral protein. Additionally, proteins that are oxidatively modified or redox-regulated will be identified. Oxidative modification is known to regulate the activities of proteins. The oxidatively modified or redox-regulated proteins may represent regulators of viral replication and pathogenesis. Once identified, these proteins will be studied for their biochemical roles and their effect on viral replication and cytopathic changes. As mitochondria lie at the hub of redox homeostasis and cellular metabolism, their dysfunction and the corresponding metabolic changes are likely to affect the cellular responses to viral infection. Using metabolomic approach, we will study the changes in metabolome of EV71-infected cells. The corresponding pathways will be functionally analyzed. Furthermore, the effect of antioxidant and metabolite supplementation on the course of viral infection will be examined. In addition, the redox microenvironment of various cellular compartments modulates cellular signaling and physiologic processes. Using RNAi as well as organelle-targeting approach, we will study if redox compartmentalization affects viral replication and pathogenesis. Moreover, oxidative stress and metabolic stress contribute to oxidative DNA damage and mutation. Through the present study, we will gain a better understanding of the relationship between oxidative stress, virus and host cells. In the era of preventive medicine, this project will open an avenue to prevention and therapy of viral infection.

Project ID:PC10301-0910
External Project ID:NSC101-2320-B182-024-MY3