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Infection and Immunity, July 2003, p. 3690-3698, Vol. 71, No. 7
0019-9567/03/$08.00+0     DOI: 10.1128/IAI.71.7.3690-3698.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Selection of Small-Colony Variants of Salmonella enterica Serovar Typhimurium in Nonphagocytic Eucaryotic Cells

David A. Cano,1,{dagger} M. Graciela Pucciarelli,2 Marina Martínez-Moya,3 Josep Casadesús,1 and Francisco García-del Portillo2*

Departamento de Genética, Facultad de Biología, Universidad de Sevilla, 41080 Seville,1 Departamento de Biotecnología Microbiana, Centro Nacional de Biotecnología, Consejo Superior de Investigaciones Científicas (CSIC), Campus de Cantoblanco,2 Centro de Biología Molecular Severo Ochoa, Universidad Autónoma de Madrid, 28049 Madrid, Spain3

Received 16 January 2003/ Returned for modification 19 March 2003/ Accepted 31 March 2003

Salmonella enterica strains are enteropathogenic bacteria that survive and proliferate within vacuolar compartments of epithelial and phagocytic cells. Recently, it has been reported that fibroblast cells are capable of restricting S. enterica serovar Typhimurium intracellular growth. Here, we show that prolonged residence of bacteria in the intracellular environment of fibroblasts results in the appearance of genetically stable small-colony variants (SCV). A total of 103 SCV isolates, obtained from four independent infections, were subjected to phenotypic analysis. The following phenotypes were observed: (i) {delta}-aminolevulinic acid auxotrophy; (ii) requirement for acetate or succinate for growth in glucose minimal medium; (iii) auxotrophy for aromatic amino acids; and (iv) reduced growth rate under aerobic conditions not linked to nutrient auxotrophy. The exact mutations responsible for the SCV phenotype in three representative isolates were mapped in the lpd, hemL, and aroD genes, which code for dihydrolipoamide dehydrogenase, glutamate-1-semyaldehyde aminotransferase, and 3-dehydroquinate dehydratase, respectively. The lpd, hemL, and aroD mutants had intracellular persistence rates in fibroblasts that were 3 to 4 logs higher than that of the parental strain and decreased susceptibility to aminoglycoside antibiotics. All three of these SCV isolates were attenuated in the BALB/c murine typhoid model. Complementation with lpd+, hem+, and aroD+ genes restored the levels of intracellular persistence and antibiotic susceptibility to levels of the wild-type strain. However, virulence was not exhibited by any of the complemented strains. Altogether, our data demonstrate that similar to what it has been reported for SCV isolates of other pathogens, S. enterica SCV display enhanced intracellular persistence in eucaryotic cells and are impaired in the ability to cause overt disease. In addition, they also suggest that S. enterica SCV may be favored in vivo.

* Corresponding author. Mailing address: Departamento de Biotecnología Microbiana, Centro Nacional de Biotecnología—CSIC, Campus de Cantoblanco, 28049 Madrid, Spain. Phone: (34) 91 5854923. Fax: (34) 91 5854506. E-mail: fgportillo{at}cnb.uam.es.

Editor: B. B. Finlay

{dagger} Present address: Diabetes Center, Department of Medicine, University of California, San Francisco, San Francisco, CA 94143-0540.

Infection and Immunity, July 2003, p. 3690-3698, Vol. 71, No. 7
0019-9567/03/$08.00+0     DOI: 10.1128/IAI.71.7.3690-3698.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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