Presenter: Prof. YANG Decheng

University: Department of Pathology and Laboratory Medicine, University of British Columbia, Institute for Heart and Lung Health, St. Paul’s Hospital, Vancouver, Canada

Time: 14:30-15:30, 26 May, 2011

Venue: A203, Institute of Microbiology, Chinese Academy of Sciences

Abstract:

Coxsackievirus B3 (CVB3) can infect multiple organs of humans and cause different diseases, such as myocarditis, pancreatitis, meningitis, etc. However, the most common disease is myocarditis. This virus infects host cells depending on the expression of viral receptor on the surface of target cells. Previous studies from our laboratory and others found that the expression levels of the viral receptor could not correlated well with the susceptibility of the corresponding host cells to the virus. This implies that other host factors may also play an important role in determining CVB3 tissue tropism and pathogenesis. MicroRNAs (miRNAs) are a group of recently discovered endogenous small RNAs regulating one third of human genes by targeting the 3’untranslated region of mRNAs. We hypothesized that cellular miRNAs may play an important role in promoting CVB3 replication in the heart and causing human viral myocarditis. To test this hypothesis, we performed microarray analyses of microRNAs using CVB3-infected mouse hearts and identified 63 up- and down-regulated microRNAs. Real time q-RT-PCR analyses further confirmed the altered expression of five miRNAs. Two miRNAs, miR-203 and miR-126 were selected for further functional study. We demonstrated that both miR-203 and miR-126 expression enhanced CVB3 replication in tissue culture cells. miR-203 promoted CVB3 replication through targeting zinc finger protein gene-148 (ZFP-148) and subsequently promoting host cell growth by inhibiting p21 and up-regulating Bcl-XL, a anti-apoptotic protein. miR-126 promoted CVB3 replication through targeting SPRED1 gene, a extracellular signal-regulated kinase (ERK) inhibitor, and subsequently enhancing host cell survival through the activated ERK survival pathway. Taken together, these data suggest that miRNA expression profile is a molecular determinant of host cell susceptibility to CVB3 infection. The up-regulated miR-203 and miR-126 play an important role in enhancing CVB3 pathogenesis.