Project Details
Abstract
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 IDs
Project ID:PC10108-0901
External Project ID:NSC101-2320-B182-024-MY3
External Project ID:NSC101-2320-B182-024-MY3
Status | Finished |
---|---|
Effective start/end date | 01/08/12 → 31/07/13 |
Keywords
- virus
- oxidative stress
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