Abstract
Redox homeostasis is an important host factor determining the outcome of infectious disease. Enterovirus 71 (EV71) infection has become an important endemic disease in Southeast Asia and China. We have previously shown that oxidative stress promotes viral replication, and progeny virus induces oxidative stress in host cells. The detailed mechanism for reactive oxygen species (ROS) generation in infected cells remains elusive. In the current study, we demonstrate that mitochondria were a major ROS source in EV71-infected cells. Mitochondria in productively infected cells underwent morphologic changes and exhibited functional anomalies, such as a decrease in mitochondrial electrochemical potential ΔΨm and an increase in oligomycin-insensitive oxygen consumption. Respiratory control ratio of mitochondria from infected cells was significantly lower than that of normal cells. The total adenine nucleotide pool and ATP content of EV71-infected cells significantly diminished. However, there appeared to be a compensatory increase in mitochondrial mass. Treatment with mito-TEMPO reduced eIF2α phosphorylation and viral replication, suggesting that mitochondrial ROS act to promote viral replication. It is plausible that EV71 infection induces mitochondrial ROS generation, which is essential to viral replication, at the sacrifice of efficient energy production, and that infected cells up-regulate biogenesis of mitochondria to compensate for their functional defect.
Highlights
Enterovirus 71 (EV71), a member of the family Picornaviridae, is a non-enveloped RNA virus [1]
As mitochondria are major sites of reactive oxygen species (ROS) generation, we test if EV71 induces ROS generation in mitochondria
Treatment of cells with apocyanin, a NADPH oxidase (NOX) inhibitor, did not affect EV71-induced ROS generation. These findings suggest that NOX is not involved in ROS generation in infected SF268 cells, and that ROS is generated at a site of mitochondrial electron transport chain distal to complex III
Summary
Enterovirus 71 (EV71), a member of the family Picornaviridae, is a non-enveloped RNA virus [1]. Clinical manifestation of EV71 infection includes febrile illness, acute respiratory disease, hand-foot-and-mouth disease, herpangia, myocarditis, aseptic meningitis, acute flaccid paralysis, brainstem and/or cerebellar encephalitis, Guillain-Barre syndrome, or combinations of these clinical features [7,8]. Though hand-foot-and-mouth disease is a benign disease, the neurologic and systemic complications are more severe [9]. Children aged below 5 years are susceptible to development of permanent neurologic sequelae, or even succumb to such complications [10]. The largest epidemic of EV71 occurred in China in 2008 and 2009. 490000 cases, of which 126 deaths occurred, were reported; over a million cases of hand-foot-and-mouth disease were reported in 2009 [4,5]. EV71 infection recurs every 2 or 3 years in Asia-Pacific region
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