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Infection and Immunity, April 1999, p. 1560-1568, Vol. 67, No. 4
0019-9567/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

The Alternative Sigma Factor, sigma E, Is Critically Important for the Virulence of Salmonella typhimurium

Sue Humphreys,1 Andrew Stevenson,1 Andrew Bacon,2 A. Barbara Weinhardt,3 and Mark Roberts1,*

Department of Veterinary Pathology, Glasgow University Veterinary School, Glasgow G61 1QH,1 and Department of Bacteriology, Glasgow Royal Infirmary, Glasgow Royal Infirmary University NHS Trust, Glasgow G4 O6F,3 and Vaccine Research Unit, Medeva, Department of Biochemistry, Imperial College of Science, Technology, and Medicine, London SW7 2AZ,2 United Kingdom

Received 26 June 1998/Returned for modification 19 August 1998/Accepted 5 January 1999

In Escherichia coli, extracytoplasmic stress is partially controlled by the alternative sigma factor, RpoE (sigma E). In response to environmental stress or alteration in the protein content of the cell envelope, sigma E upregulates the expression of a number of genes, including htrA. It has been shown that htrA is required for intramacrophage survival and virulence in Salmonella typhimurium. To investigate whether sigma E-regulated genes other than htrA are involved in salmonella virulence, we inactivated the rpoE gene of S. typhimurium SL1344 by allelic exchange and compared the phenotype of the mutant (GVB311) in vitro and in vivo with its parent and an isogenic htrA mutant (BRD915). Unlike E. coli, sigma E is not required for the growth and survival of S. typhimurium at high temperatures. However, GVB311 did display a defect in its ability to utilize carbon sources other than glucose. GVB311 was more sensitive to hydrogen peroxide, superoxide, and antimicrobial peptides than SL1344 and BRD915. Although able to invade both macrophage and epithelial cell lines normally, the rpoE mutant was defective in its ability to survive and proliferate in both cell lines. The effect of the rpoE mutation on the intracellular behavior of S. typhimurium was greater than that of the htrA mutation. Both GVB311 and BRD915 were highly attenuated in mice. Neither strain was able to kill mice via the oral route, and the 50% lethal dose (LD50) for both strains via the intravenous (i.v.) route was very high. The i.v. LD50s for SL1344, BRD915, and GVB311 were <10, 5.5 × 105, and 1.24 × 107 CFU, respectively. Growth in murine tissues after oral and i.v. inoculation was impaired for both the htrA and rpoE mutant, with the latter mutant being more severely affected. Neither mutant was able to translocate successfully from the Peyer's patches to other organs after oral infection or to proliferate in the liver and spleen after i.v. inoculation. However, the htrA mutant efficiently colonized the livers and spleens of mice infected i.v., but the rpoE mutant did not. Previous studies have shown that salmonella htrA mutants are excellent live vaccines. In contrast, oral immunization of mice with GVB311 was unable to protect any of the mice from oral challenge with SL1344. Furthermore, i.v. immunization with a large dose (~106 CFU) of GVB311 protected less than half of the orally challenged mice. Thus, our results indicate that genes in the sigma E regulon other than htrA play a critical role in the virulence and immunogenicity of S. typhimurium.

* Corresponding author. Mailing address: Department of Veterinary Pathology, Glasgow University Veterinary School, Bearsden Rd., Glasgow G61 1QH, United Kingdom. Phone: 0141-330-5780. Fax: 0141-330-5602. E-mail: M.Roberts{at}vet.gla.ac.uk.

Infection and Immunity, April 1999, p. 1560-1568, Vol. 67, No. 4
0019-9567/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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