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Journal of Virology, September 2009, p. 9356-9369, Vol. 83, No. 18
0022-538X/09/$08.00+0     doi:10.1128/JVI.02382-07
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Viral Persistence and Chronic Immunopathology in the Adult Central Nervous System following Coxsackievirus Infection during the Neonatal Period

Ralph Feuer,^4* Chelsea M. Ruller,⁴ Naili An,¹ Jenna M. Tabor-Godwin,⁴ Ross E. Rhoades,⁴ Sonia Maciejewski,⁴ Robb R. Pagarigan,¹ Christopher T. Cornell,^1, Stephen J. Crocker,^1, William B. Kiosses,² Ngan Pham-Mitchell,¹ Iain L. Campbell,³ and J. Lindsay Whitton¹

Department of Immunology and Microbial Science, SP30-2110, North Torrey Pines Road, La Jolla, California 92037,¹ Core Microscopy Facility, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037,² School of Molecular and Microbial Biosciences, University of Sydney, Sydney, Australia,³ Department of Biology, San Diego State University, San Diego, California 92182-4614⁴

Received 3 November 2007/ Accepted 3 June 2009

Coxsackieviruses are significant human pathogens, and the neonatal central nervous system (CNS) is a major target for infection. Despite the extreme susceptibility of newborn infants to coxsackievirus infection and viral tropism for the CNS, few studies have been aimed at determining the long-term consequences of infection on the developing CNS. We previously described a neonatal mouse model of coxsackievirus B3 (CVB3) infection and determined that proliferating stem cells in the CNS were preferentially targeted. Here, we describe later stages of infection, the ensuing inflammatory response, and subsequent lesions which remain in the adult CNS of surviving animals. High levels of type I interferons and chemokines (in particular MCP-5, IP10, and RANTES) were upregulated following infection and remained at high levels up to day 10 postinfection (p.i). Chronic inflammation and lesions were observed in the hippocampus and cortex of surviving mice for up to 9 months p.i. CVB3 RNA was detected in the CNS up to 3 months p.i at high abundance (10⁶ genomes/mouse brain), and viral genomic material remained detectable in culture after two rounds of in vitro passage. These data suggest that CVB3 may persist in the CNS as a low-level, noncytolytic infection, causing ongoing inflammatory lesions. Thus, the effects of a relatively common infection during the neonatal period may be long lasting, and the prognosis for newborn infants recovering from acute infection should be reexplored.

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* Corresponding author. Mailing address: Cell and Molecular Biology Joint Doctoral Program, Department of Biology, San Diego State University, 5500 Campanile Drive, San Diego, CA 92182-4614. Phone: (619) 594-7377. Fax: (619) 594-0777. E-mail: rfeuer{at}sciences.sdsu.edu

Published ahead of print on 1 July 2009.

Present address: Biopharmaceutical Department, Allergan, Inc., 2525 Dupont Dr., Irvine, CA 92612.

Present address: Department of Neuroscience, Faculty of Medicine, University of Connecticut Health Center, Farmington, CT 06030-3401.

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Journal of Virology, September 2009, p. 9356-9369, Vol. 83, No. 18
0022-538X/09/$08.00+0     doi:10.1128/JVI.02382-07
Copyright © 2009, American Society for Microbiology. All Rights Reserved.