JVI Accepts, published online ahead of print on 2 July 2008

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J. Virol. doi:10.1128/JVI.00641-08
Copyright (c) 2008, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Autophagosome Supports Coxsackievirus B3 Replication In Host Cells

Jerry Wong, Jingchun Zhang, Xiaoning Si, Guang Gao, Ivy Mao, Bruce M. McManus, and Honglin Luo^*

The James Hogg iCAPTURE Centre for Cardiovascular and Pulmonary Research, Department of Pathology and Laboratory Medicine, University of British Columbia, Providence Heart + Lung Institute, St. Paul's Hospital, Vancouver, BC, Canada

^* To whom correspondence should be addressed. Email: hluo{at}mrl.ubc.ca.

Recent studies suggest a possible takeover of host anti-microbial autophagy machinery by positive-stranded RNA viruses to facilitate their own replication. In the present study, we investigated the role of autophagy in coxsackievirus replication. Coxsackievirus B3 (CVB3), a picornavirus associated with viral myocarditis, causes pronounced intracellular membrane reorganization after infection. We demonstrate that CVB3 infection induces increased numbers of double-membrane vesicles, which is accompanied by an increase of LC3-II/LC3-I ratio and an accumulation of punctate GFP-LC3 cells, two hallmarks of cellular autophagosome formation. However, protein expression analysis of p62, a marker for autophagy-mediated protein degradation, showed no apparent changes after CVB3 infection. These results suggest that CVB3 infection triggers autophagosome formation without promoting protein degradation by the lysosome. We further examined the role of autophagosome in CVB3 replication. We demonstrated that inhibition of autophagosome formation by 3-methyladenine or small-interfering RNA targeting the genes critical for autophagosome formation (ATG7, Beclin-1, and VPS34) significantly reduced viral replication. Conversely, induction of autophagy by rapamycin or nutrient deprivation resulted in increased viral replication. Finally, we examined the role of autophagosome-lysosome fusion in viral replication. We showed that blockage of the fusion by gene-silencing of lysosomal protein LAMP2 significantly promoted viral replication. Taken together, our results suggest that host's autophagy machinery is activated during CVB3 infection to enhance the efficiency of viral replication.

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