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Regulation of host immune responses by modification of Salmonella virulence genes

Nature Medicine volume 4, pages 1247–1252 (1998)Cite this article

Abstract

Modifying bacterial virulence genes to probe the nature of host immunity is mostly unexplored. Here we investigate whether host immune responses can be regulated by modification of bacterial virulence genes. In mice, attenuated Salmonella mutant strains with clinical relevance elicited differential host immune responses. Oral administration of a mutant strain with a PhoP-null phenotype promoted potent innate immune responses of macrophages that were sufficient for host defense. In contrast, administration of an Aro – mutant strain elicited stronger specific antibody and T-helper (Th)-cell responses, wherein Th1-type cells were required for clearance. Thus, genetic manipulation of bacteria may be used to broadly alter immune mechanisms that regulate attenuation within the host and to tailor host immunity to specific bacterial pathogens.

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Figure 1: Susceptibilities of normal and IFN-γ–/– mice to infection with Aro–and PhoP– S. typhimurium.
Figure 2: Th1- and Th2-type cytokine profiles and antibody responses in normal and IFN-γ–/– mice inoculated with Aro–and PhoP– strains of S. typhimurium or uninoculated (naive).
Figure 3: Effect of S. typhimurium mutant strains and wild-type bacteria on antimicrobial production in IFN-γ+/+, IFN-γ–/– and TCR-β × δ–/– mice.
Figure 4: Effects of L-NIL, allopurinol, TNF-α neutralization and recombinant TNF-α on the virulence of Aro– and PhoP– S. typhimurium in mice.
Figure 5: Effect of S. typhimurium mutant strains and wild-type bacteria on inflammatory responses in normal and IFN-γ–/– mice.

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Acknowledgements

We thank F. Fang for critical reading of the manuscript, B. Stocker for construction of strain SL7731 for these studies, and A. Szalai for running SAP ELISA. This work was supported by NIH grants AI 18958, DK 44240, RR 13149 and USDA grant 9602195, as well as grants from the Ministry of Education, Science, Sports and Culture and OPSR in Japan.

Author information

Authors and Affiliations

  1. Division of Infectious Disease, Children's Hospital Medical Center, Cincinnati, 45229, Ohio, USA

    John L. VanCott

  2. Department of Biochemistry Imperial College of Science, Vaccine Research Unit, MEDEVA, Technology and Medicine, London, SW7 2AY, United Kingdom

    Stephen N. Chatfield

  3. Department of Veterinary Pathology, University of Glasgow, Bearsden Rd, Glasgow, G61 1QH

    Mark Roberts

  4. Division of Vaccine Research, Institute of Human Virology, Baltimore, 21201, Maryland, USA

    David M. Hone

  5. Infectious Disease Division, Massachusetts General Hospital, Boston, 02114, Massachusetts, USA

    Elizabeth L. Hohmann

  6. Veterinary Molecular Biology, Montana State University , Bozeman, 59717-3610, Montana, USA

    David W. Pascual

  7. Department of Mucosal Immunology, Research Institute for Microbial Diseases, Osaka University, Osaka, 565 , Japan

    Masafumi Yamamoto & Hiroshi Kiyono

  8. Department of Microbiology, The Immunobiology Vaccine Center, The University of Alabama at Birmingham, Birmingham, 35294, Alabama, USA

    Jerry R. McGhee

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VanCott, J., Chatfield, S., Roberts, M. et al. Regulation of host immune responses by modification of Salmonella virulence genes. Nat Med 4, 1247–1252 (1998). https://doi.org/10.1038/3227

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