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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,
Craig J.
Lipps,1
Renee M.
Tsolis,1,
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.

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

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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