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Infect Immun, July 1998, p. 3372-3377, Vol. 66, No. 7
0019-9567/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

At Least Four Percent of the Salmonella typhimurium Genome Is Required for Fatal Infection of Mice

Frances Bowe,1,dagger Craig J. Lipps,1 Renee M. Tsolis,1,Dagger Eduardo Groisman,2 Fred Heffron,1,* and Johannes G. Kusters1,§

Department of Molecular Microbiology and Immunology, Oregon Health Sciences University, Portland, Oregon 97201,1 and Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, Missouri 631102

Received 15 December 1997/Returned for modification 19 February 1998/Accepted 20 April 1998

Salmonella typhimurium infection of mice is an established model system for studying typhoid fever in humans. Using this model, we identified S. typhimurium genes which are absolutely required to cause fatal murine infection by testing independently derived transposon insertion mutants for loss of virulence in vivo. Of the 330 mutants tested intraperitoneally and the 197 mutants tested intragastrically, 12 mutants with 50% lethal doses greater than 1,000 times that of the parental strain were identified. These attenuated mutants were characterized by in vitro assays which correlate with known virulence functions. In addition, the corresponding transposon insertions were mapped within the S. typhimurium genome and the nucleotide sequence of the transposon-flanking DNA was obtained. Salmonella spp. and related bacteria were probed with flanking DNA for the presence of these genes. All 12 attenuated mutants had insertions in known genes, although the attenuating effects of only two of these were previously described. Furthermore, the proportion of attenuated mutants obtained in this study suggests that mutations in about 4% of the Salmonella genome lead to 1,000-fold or greater attenuation in the mouse typhoid model of infection. Most of these genes appear to be required during the early stages of a natural infection.

* Corresponding author. Mailing address: Department of Molecular Microbiology and Immunology, Oregon Health Sciences University, 3181 SW Sam Jackson Park Rd., Portland, OR 97201. Phone: (503) 494-6738. Fax: (503) 494-6862. E-mail: heffronf{at}ohsu.edu.

dagger Present address: Biochemistry Department, Imperial College of Science, Technology and Medicine, London SW7 2AZ, England.

Dagger Present address: Department of Veterinary Medicine, Texas A & M University, College Station, TX 77843.

§ Present address: Department of Medical Microbiology, Vrije Universiteit, 1081 BT Amsterdam, The Netherlands.

Infect Immun, July 1998, p. 3372-3377, Vol. 66, No. 7
0019-9567/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.


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