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Journal of Virology, October 2002, p. 9900-9909, Vol. 76, No. 19
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.19.9900-9909.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Biological Significance of a Human Enterovirus B-Specific RNA Element in the 3' Nontranslated Region

Ingrid Merkle,1 Mark J. M. van Ooij,2 Frank J. M. van Kuppeveld,2 Dirk H. R. F. Glaudemans,2 Jochem M. D. Galama,2 Andreas Henke,1 Roland Zell,1 and Willem J. G. Melchers2*

Institute of Virology, Friedrich Schiller University, D-07745 Jena, Germany,1 Department of Medical Microbiology, Nijmegen Center for Molecular Life Science, University Medical Center Nijmegen, 6500 HB Nijmegen, The Netherlands2

Received 7 March 2002/ Accepted 24 June 2002

The secondary structures predicted for the enteroviral 3' nontranslated region (3'NTR) all seem to indicate a conformation consisting of two (X and Y) hairpin structures. The higher-order RNA structure of the 3'NTR appears to exist as an intramolecular kissing interaction between the loops of these two hairpin structures. The enterovirus B-like subgroup possesses an additional stem-loop structure, domain Z, which is not present in the poliovirus-like enteroviruses. It has been suggested that the Z domain originated from a burst of short sequence repetitions (E. V. Pilipenko, S. V. Maslova, A. N. Sinyakov, and V. I. Agol, Nucleic Acids Res. 20:1739-1745, 1992). However, no functional features have yet been ascribed to this enterovirus B-like-specific RNA element in the 3'NTR. In this study, we tested the functional characteristics and biological significance of domain Z. A mutant of the cardiovirulent coxsackievirus group B3 strain Nancy which completely lacked the Z domain and which therefore acquired enterovirus C-like secondary structures exhibited a wild-type growth phenotype, as determined by single-cycle growth analysis with BGM cells. This result proves that the Z domain is virtually dispensable for viral growth in tissue cultures. Partial distortion of the Z domain structure resulted in a disabled virus with reduced growth kinetics, probably due to alternative conformations of the overall structure of the domain. Infection of mice showed that the recombinant coxsackievirus group B3 mutant which completely lacked the Z domain was less virulent. Pancreatic tissues from mice infected with wild-type virus and recombinant virus were equally affected. However, the heart tissue from mice infected with the recombinant virus showed only slight signs of myocarditis. These results suggest that the enterovirus B-like-specific Z domain plays a role in coxsackievirus-induced pathogenesis.

* Corresponding author. Mailing address: University Medical Center Nijmegen, Nijmegen Center for Molecular Life Science, Department of Medical Microbiology, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands. Phone: 31-24-3614356. Fax: 31-24-3540216. E-mail: w.melchers{at}NCMLS.kun.nl.

Journal of Virology, October 2002, p. 9900-9909, Vol. 76, No. 19
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.19.9900-9909.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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