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Infection and Immunity, May 2001, p. 3021-3030, Vol. 69, No. 5
0019-9567/01/$04.00+0   DOI: 10.1128/IAI.69.5.3021-3030.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Flagellar Phase Variation of Salmonella enterica Serovar Typhimurium Contributes to Virulence in the Murine Typhoid Infection Model but Does Not Influence Salmonella-Induced Enteropathogenesis

Jack S. Ikeda,1,dagger Clare K. Schmitt,1,Dagger Stephen C. Darnell,1 Patricia R. Watson,2 Jennifer Bispham,2 Timothy S. Wallis,2 Debra L. Weinstein,1 Eleanor S. Metcalf,1 Phillip Adams,3,§ C. David O'Connor,3 and Alison D. O'Brien1,*

Department of Microbiology and Immunology, Uniformed Services University of the Health Sciences, F. Edward Hebert School of Medicine, Bethesda, Maryland 20814,1 and Institute for Animal Health, Compton, Newbury, Berkshire RG20 7NN,2 and Division of Biochemistry and Molecular Biology, School of Biological Sciences, University of Southampton, Southampton SO16 7PX,3 United Kingdom

Received 11 October 2000/Returned for modification 28 November 2000/Accepted 16 January 2001

Although Salmonella enterica serovar Typhimurium can undergo phase variation to alternately express two different types of flagellin subunit proteins, FljB or FliC, no biological function for this phenomenon has been described. In this investigation, we constructed phase-locked derivatives of S. enterica serovar Typhimurium that expressed only FljB (termed locked-ON) or FliC (termed locked-OFF). The role of phase variation in models of enteric and systemic pathogenesis was then evaluated. There were no differences between the wild-type parent strain and the two phase-locked derivatives in adherence and invasion of mouse epithelial cells in vitro, survival in mouse peritoneal macrophages, or in a bovine model of gastroenteritis. By contrast, the locked-OFF mutant was virulent in mice following oral or intravenous (i.v.) inoculation but the locked-ON mutant was attenuated. When these phase-locked mutants were compared in studies of i.v. kinetics in mice, similar numbers of the two strains were isolated from the blood and spleens of infected animals at 6 and 24 h. However, the locked-OFF mutant was recovered from the blood and spleens in significantly greater numbers than the locked-ON strain by day 2 of infection. By 5 days postinfection, a majority of the mice infected with the locked-OFF mutant had died compared with none of the mice infected with the locked-ON mutant. These results suggest that phase variation is not involved in the intestinal stage of infection but that once S. enterica serovar Typhimurium reaches the spleens of susceptible mice those organisms in the FliC phase can grow and/or survive better than those in the FljB phase. Additional experiments with wild-type S. enterica serovar Typhimurium, fully capable of switching flagellin type, supported this hypothesis. We conclude that organisms that have switched to the FliC+ phase have a selective advantage in the mouse model of typhoid fever but have no such advantage in invasion of epithelial cells or the induction of enteropathogenesis.

* Corresponding author. Mailing address: Department of Microbiology and Immunology, Uniformed Services University of the Health Sciences, F. Edward Hebert School of Medicine, 4301 Jones Bridge Rd., Bethesda, MD 20814. Phone: (301) 295-3419. Fax: (301) 295-3773. E-mail: aobrien{at}usuhs.mil.

dagger Present address: Department of Animal Sciences, Colorado State University, Fort Collins, CO 80523.

Dagger Present address: National Institutes of Health, Center for Scientific Review, Bethesda, MD 20892.

§ Present address: Argonex Discovery, Gemini Cresent, Dundee Technology Park, Dundee DD2 1SW, Scotland.

Infection and Immunity, May 2001, p. 3021-3030, Vol. 69, No. 5
0019-9567/01/$04.00+0   DOI: 10.1128/IAI.69.5.3021-3030.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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