The Role of Host's Redox Status in Host-Pathogen Interactions

Variations in host microenvironment affect the infectivity of pathogen and thus the outcome of infection. The roles of certain host factors such as redox status remain elusive. Using enterovirus 71 (EV71) as model, we have recently shown that the redox status of host cells affects the viral replication and hence pathogenesis. Replication of EV71 was significantly enhanced in G6PD-deficient cells, which have lowered NADPH/NADP+ and glutathione/glutathione disulfide ratios. Levels of viral RNA and protein, as well as production of progeny virions, significantly increased in these cells. Concomitant with these changes, EV71 infection elicited oxidative stress. We hypothesize that EV71 infection results in a vicious cycle of reactive oxygen species production and viral replication. One of the aims of the present proposal is to study mechanistic aspects of such cycle. Virus-induced oxidative stress was preceded by mitochondrial dysfunction, and could be mimicked by expression of viral proteins. It is likely that mitochondrial dysfunction and ROS generation occur as a consequence of interactions between EV71 viral proteins and host proteins, especially those of mitochondria. One of the aims of the present proposal is to identify host proteins interacting with EV71 viral proteins. In addition, using proteomic approach, the host and viral proteins that undergo oxidative post-translational modifications or are redox-regulated will be determined. The biochemical roles of these proteins and their effects on viral replication will be studied in detail. Additionally, redox-regulated signaling pathways, like mitogen-activated protein kinases and related kinases, will be thoroughly studied. Moreover, antioxidant enzymes in various sub-cellular compartments may differentially modulate the redox status of local milieu, which in turn affects viral virulence. Another aim of the present proposal is to dissect the roles of different antioxidant genes in viral replication using genetic and pharmacological approaches. It is wondered whether overall redox status affects viral replication and the outcome of infection in vivo. A murine model of EV71 infection will be used, and the proteomes of different tissues will be examined. The proteome of oxidatively modified proteins as well as oxidative damage markers, such as nitrotyrosine and protein carbonyl, will also be studied. Proteins showing differential expression or oxidative post-translational modifications will be studied through biochemical and/or functional approaches. Furthermore, extracts or purified compounds of medicinal herbs will be screened for their antioxidant and antiviral activities. Though the present proposal aims to reveal the effects of cellular redox status on EV71 pathogenesis, the findings to be obtained can be generalized to the studies of other viruses. Through the present study, we will gain a better understanding of the role of reactive oxygen species in viral infection. In prospect, this project may pave a new way for antioxidant intervention in EV71 infection as well as other viral infections.

Project ID:PC9801-2498
External Project ID:NSC97-2320-B182-015-MY3