Penton-dodecahedral particles trigger opening of intercellular junctions and facilitate viral spread during adenovirus serotype 3 infection of epithelial cells

Human adenovirus serotypes Ad3, Ad7, Ad11, and Ad14 use the epithelial junction protein desmoglein 2 (DSG2) as a receptor for infection. During Ad infection, the fiber and penton base capsid proteins are produced in vast excess and form hetero-oligomers, called pentons. It has been shown for Ad3 tha...

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Published in:	PLoS pathogens 2013-10, Vol.9 (10), p.e1003718-e1003718
Main Authors:	Lu, Zhuo-Zhuang, Wang, Hongjie, Zhang, Yiyi, Cao, Hua, Li, Zongyi, Fender, Pascal, Lieber, André
Format:	Article
Language:	eng
Subjects:	Adenovirus Infections, Human Adenovirus Infections, Human - genetics Adenovirus Infections, Human - metabolism Adenovirus Infections, Human - transmission Adenoviruses Adenoviruses, Human Adenoviruses, Human - genetics Adenoviruses, Human - metabolism Animals Atoms & subatomic particles Biochemistry, Molecular Biology Cancer Crystal structure Epithelial Cells Epithelial Cells - metabolism Epithelial Cells - pathology Epithelial Cells - virology Health aspects HeLa Cells Host-parasite relationships Humans Intercellular Junctions Intercellular Junctions - metabolism Intercellular Junctions - pathology Intercellular Junctions - virology Kinases Life Sciences Mice Neoplasms Neoplasms - metabolism Neoplasms - pathology Neoplasms - therapy Oncolytic Virotherapy Oncolytic Virotherapy - methods Physiological aspects Proteins Structural Biology Sucrose Virion Virion - metabolism Viruses
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Summary:	Human adenovirus serotypes Ad3, Ad7, Ad11, and Ad14 use the epithelial junction protein desmoglein 2 (DSG2) as a receptor for infection. During Ad infection, the fiber and penton base capsid proteins are produced in vast excess and form hetero-oligomers, called pentons. It has been shown for Ad3 that pentons self-assemble into penton-dodecahedra (PtDd). Our previous studies with recombinant purified Ad3 PtDd (produced in insect cells) showed that PtDd bind to DSG2 and trigger intracellular signaling resulting in the transient opening of junctions between epithelial cells. So far, a definitive proof for a function of Ad3 PtDd in the viral life cycle is elusive. Based on the recently published 3D structure of recombinant Ad3 PtDd, we generated a penton base mutant Ad3 vector (mu-Ad3GFP). mu-Ad3GFP is identical to its wild-type counterpart (wt-Ad3GFP) in the efficiency of progeny virus production; however, it is disabled in the production of PtDd. For infection studies we used polarized epithelial cancer cells or cell spheroids. We showed that in wt-Ad3GFP infected cultures, PtDd were released from cells before viral cytolysis and triggered the restructuring of epithelial junctions. This in turn facilitated lateral viral spread of de novo produced virions. These events were nearly absent in mu-Ad3GFP infected cultures. Our in vitro findings were consolidated in mice carrying xenograft tumors derived from human epithelial cancer cells. Furthermore, we provide first evidence that PtDd are also formed by another DSG2-interacting Ad serotype, the newly emerged, highly pathogenic Ad14 strain (Ad14p1). The central finding of this study is that a subgroup of Ads has evolved to generate PtDd as a strategy to achieve penetration into and dissemination in epithelial tissues. Our findings are relevant for basic and applied virology, specifically for cancer virotherapy.
ISSN:	1553-7374 1553-7366 1553-7374