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Infection and Immunity, October 2001, p. 6463-6474, Vol. 69, No. 10
0019-9567/01/$04.00+0   DOI: 10.1128/IAI.69.10.6463-6474.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Salmonella enterica Serovar Typhimurium Response Involved in Attenuation of Pathogen Intracellular Proliferation

David A. Cano,1 Marina Martínez-Moya,2,dagger M. Graciela Pucciarelli,2,Dagger Eduardo A. Groisman,3 Josep Casadesús,1 and Francisco García-Del Portillo2,*

Departamento de Genética, Facultad de Biología, Universidad de Sevilla, 41080 Seville,1 and Centro de Biología Molecular "Severo Ochoa," CSIC-Universidad Autónoma de Madrid, 28049 Madrid,2 Spain, and Howard Hughes Medical Institute, Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, Missouri 63110-10933

Received 30 March 2001/Returned for modification 4 June 2001/Accepted 4 July 2001

Salmonella enterica serovar Typhimurium proliferates within cultured epithelial and macrophage cells. Intracellular bacterial proliferation is, however, restricted within normal fibroblast cells. To characterize this phenomenon in detail, we investigated the possibility that the pathogen itself might contribute to attenuating the intracellular growth rate. S. enterica serovar Typhimurium mutants were selected in normal rat kidney fibroblasts displaying an increased intracellular proliferation rate. These mutants harbored loss-of-function mutations in the virulence-related regulatory genes phoQ, rpoS, slyA, and spvR. Lack of a functional PhoP-PhoQ system caused the most dramatic change in the intracellular growth rate. phoP- and phoQ-null mutants exhibited an intracellular growth rate 20- to 30-fold higher than that of the wild-type strain. This result showed that the PhoP-PhoQ system exerts a master regulatory function for preventing bacterial overgrowth within fibroblasts. In addition, an overgrowing clone was isolated harboring a mutation in a previously unknown serovar Typhimurium open reading frame, named igaA for intracellular growth attenuator. Mutations in other serovar Typhimurium virulence genes, such as ompR, dam, crp, cya, mviA, spiR (ssrA), spiA, and rpoE, did not result in pathogen intracellular overgrowth. Nonetheless, lack of either SpiA or the alternate sigma factor RpoE led to a substantial decrease in intracellular bacterial viability. These results prove for the first time that specific serovar Typhimurium virulence regulators are involved in a response designed to attenuate the intracellular growth rate within a nonphagocytic host cell. This growth-attenuating response is accompanied by functions that ensure the viability of intracellular bacteria.

* 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.

dagger Present address: Fraunhofer Institut für Grenzflächen-und Bioverfahrenstechnik, D-70569, Stuttgart, Germany.

Dagger Present address: Departamento de Biotecnología Microbiana, Centro Nacional de Biotecnología, Consejo Superior de Investigaciones Científicas (CSIC), Campus de Cantoblanco, 28049 Madrid, Spain.

Infection and Immunity, October 2001, p. 6463-6474, Vol. 69, No. 10
0019-9567/01/$04.00+0   DOI: 10.1128/IAI.69.10.6463-6474.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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