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Infection and Immunity, October 2006, p. 5914-5925, Vol. 74, No. 10
0019-9567/06/$08.00+0     doi:10.1128/IAI.00619-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Down-Regulation of Key Virulence Factors Makes the Salmonella enterica Serovar Typhimurium rfaH Mutant a Promising Live-Attenuated Vaccine Candidate{dagger}

Gábor Nagy,1,2* Vittoria Danino,3 Ulrich Dobrindt,2 Mark Pallen,4 Roy Chaudhuri,4 Levente Emödy,1 Jay C. Hinton,3 and Jörg Hacker2

Department of Medical Microbiology and Immunology, University of Pécs, Szigeti út 12, 7624 Pécs, Hungary,1 Institute for Molecular Biology of Infectious Diseases, University of Würzburg, Röntgenring 11, 97070 Würzburg, Germany,2 Institute of Food Research, Norwich Research Park, Colney, Norwich NR4 7UA, United Kingdom,3 Division of Immunity & Infection, Medical School, University of Birmingham, Birmingham B15 2TT, United Kingdom4

Received 17 April 2006/ Returned for modification 31 May 2006/ Accepted 25 July 2006

Mutants of Salmonella enterica serovar Typhimurium that lack the transcriptional regulator RfaH are efficient as live oral vaccines against salmonellosis in mice. We show that the attenuation of the vaccine candidate strain is associated with reduced net growth in epithelial and macrophage cells. In order to identify the relevant RfaH-dependent genes, the RfaH regulon was determined with S. enterica serovars Enteritidis and Typhimurium using whole-genome Salmonella microarrays. As well as impacting the expression of genes involved in lipopolysaccharide (LPS) core and O-antigen synthesis, the loss of RfaH results in a marked down-regulation of SPI-4 genes, the flagellum/chemotaxis system, and type III secretion system 1. However, a proportion of these effects could have been the indirect consequence of the altered expression of genes required for LPS biosynthesis. Direct and indirect effects of the rfaH mutation were dissociated by genome-wide transcriptional profiling of a structural deep-rough LPS mutant (waaG). We show that truncation of LPS itself is responsible for the decreased intracellular yield observed for {Delta}rfaH strains. LPS mutants do not differ in replication ability; rather, they show increased susceptibility to antimicrobial peptides in the intracellular milieu. On the other hand, evidence that deletion of rfaH, as well as some other genes involved in LPS biosynthesis, results in enhanced invasion of various mammalian cells is shown. Exposure of common minor antigens in the absence of serovar-specific antigens might be responsible for the observed cross-reactive nature of the elicited immune response upon vaccination. Increased invasiveness of the Salmonella rfaH mutant into antigen-presenting cells, combined with increased intracellular killing and the potential for raising a cross-protective immune response, renders the rfaH mutant an ideal vaccine candidate.

* Corresponding author. Mailing address: Department of Medical Microbiology and Immunology, University of Pécs, Szigeti út 12, 7624 Pécs, Hungary. Phone: 36-305776629. Fax: 36-72536253. E-mail: gabor.nagy{at}aok.pte.hu.

{dagger} Supplemental material for this article may be found at http://iai.asm.org/.

Editor: A. D. O'Brien

Infection and Immunity, October 2006, p. 5914-5925, Vol. 74, No. 10
0019-9567/06/$08.00+0     doi:10.1128/IAI.00619-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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