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Journal of Virology, December 1999, p. 10440-10446, Vol. 73, No. 12
0022-538X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

A Single Nucleotide Change in the 5' Noncoding Region of Sindbis Virus Confers Neurovirulence in Rats

David Kobiler,1 Charles M. Rice,2 Chaya Brodie,3 Abraham Shahar,1 Jean Dubuisson,4 Menahem Halevy,1 and Shlomo Lustig1,*

Department of Infectious Diseases, Israel Institute for Biological Research, Ness Ziona 74100, Israel1; Department of Molecular Biology, Washington University School of Medicine, St. Louis, Missouri 63110-10932; Department of Life Sciences, Bar-Ilan University, Ramat-Gan 52900, Israel3; and Institut de Biologie and Institut Pasteur de Lille, CNRS-UMR 8526, 59021 Lille Cedex, France4

Received 6 May 1999/Accepted 11 August 1999

Two pairs of Sindbis virus (SV) variants that differ in their neuroinvasive and neurovirulent traits in mice have been isolated. Recently, we mapped the genetic determinants responsible for neuroinvasiveness in weanling mice. Here, we extend this study to newborn and adult rats and to rat neuronal cultures. Remarkably, certain aspects of the pathogenesis of these strains in rats were found to be quite distinct from the mouse model. Suckling rats were susceptible to all four isolates, and replication in the brain was observed after both intraperitoneal and intracranial (i.c.) inoculation. None of the isolates was neuroinvasive in adult rats, although all replicated after i.c. inoculation. For the isolate pair that was highly neurovirulent in mice, SVN and SVNI, only SVNI caused death after i.c. inoculation of adult rats. Similarly, only SVNI was cytotoxic for primary cultures of mature neurons. The genetic determinants responsible for the pathogenic properties of SVNI were mapped to the E2 glycoprotein and the 5' noncoding region (5'NCR). Substitution of two amino acids in SVN E2 with the corresponding residues of SVNI (Met-190 and Lys-260) led to paralysis in 3- and 5-week-old rats. More dramatically, a single substitution in the 5'NCR of SVN (G at position 8) transformed the virus into a lethal pathogen for 3-week-old rats like SVNI. In 5-week-old rats, however, this recombinant was attenuated relative to SVNI by 2 orders of magnitude. Combination of the E2 and 5'NCR determinants resulted in a recombinant with virulence properties indistinguishable from those of SVNI. These data indicate that the 5'NCR and E2 play an instrumental role in determining the age-dependent pathogenic properties of SV in rats.

* Corresponding author. Mailing address: Department of Infectious Diseases, Israel Institute for Biological Research, P.O.B. 19, Ness-Ziona 74100, Israel. Phone: 972-8-9381646. Fax: 972-8-9401094. E-mail: kobiler{at}iibr.gov.il.

Journal of Virology, December 1999, p. 10440-10446, Vol. 73, No. 12
0022-538X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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