Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Acquired Diseases
  • Published:

In vivo correction of genetic defects of monocyte/ macrophages using attenuated Salmonella as oral vectors for targeted gene delivery

Gene Therapy volume 7, pages 1725–1730 (2000)Cite this article

Abstract

Macrophages are normal targets for Salmonella during natural infections, and it has been demonstrated that attenuated bacteria can deliver nucleic acid vaccine constructs. Therefore, we assessed if attenuated Salmonella can be used for the in vivo delivery of transgenes to their natural cellular target, in an attempt to correct genetic defects associated with monocytes/macrophages. This system would offer the distinct advantage of achieving a specific targeting of defective cells in a non-invasive form. Using a reporter gene, we demonstrated that attenuated Salmonella could be used as an effective in vitro delivery system to transfer genetic material into nondividing cells like murine macrophages. In vivo, the oral administration of attenuated Salmonella allows targeted delivery of transgenes to macrophages and subsequently expression of transgenes at a systemic level. IFNγ-deficient mice (GKO) were thus selected as a model for the in vivo validation of the Salmonella-based delivery approach. Attenuated Salmonella, used as the carrier for a eukaryotic expression vector encoding the murine IFNγ gene, was able to restore the production of this cytokine in GKO macrophages. Their oral administration to IFNγ-deficient mice also re-established, in these immunocompromised animals, the natural resistance to bacterial infections. These results demonstrate, for the first time, that attenuated Salmonella can be successfully used in vivo as a DNA delivery system for the correction of a genetic defect associated with monocyte/macrophages.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4

Similar content being viewed by others

References

  1. Malech HL, Bauer TR Jr, Hickstein DD . Prospects for gene therapy of neutrophil defects Semin Hematol 1997 34: 355–361

    CAS  PubMed  Google Scholar 

  2. Meischl C, Roos D . The molecular basis of chronic granulomatous disease Springer Semin Immunopathol 1998 19: 417–434

    Article  CAS  PubMed  Google Scholar 

  3. Platt F, Butters TD . New therapeutic prospects for the glycosphingolipid lysosomal storage diseases Biochem Pharmacol 1998 56: 421–430

    Article  CAS  PubMed  Google Scholar 

  4. Grillot-Courvalin C et al. Functional gene transfer from intracellular bacteria to mammalian cells Nat Biotechnol 1998 16: 862–866

    Article  CAS  PubMed  Google Scholar 

  5. Grillot-Courvalin C, Goussard S, Courvalin P . Bacteria as gene delivery vectors for mammalian cells Curr Opin Biotechnol 1999 10: 477–481

    Article  CAS  PubMed  Google Scholar 

  6. Sizemore DR, Branstrom AA, Sadoff JC . Attenuated Shigella as a DNA delivery vehicle for DNA-mediated immunization Science 1995 270: 299–302

    Article  CAS  PubMed  Google Scholar 

  7. Hackett J . Use of Salmonella for heterologous gene expression and vaccine delivery systems Curr Opin Biotechnol 1993 4: 611–615

    Article  CAS  PubMed  Google Scholar 

  8. Darji A et al. Oral somatic transgene vaccination using attenuated S. typhimurium Cell 1997 91: 765–775

    Article  CAS  PubMed  Google Scholar 

  9. Medina E et al. Salmonella vaccine carrier strains: effective delivery system to trigger anti-tumor immunity by oral route Eur J Immunol 1999 29: 693–699

    Article  CAS  PubMed  Google Scholar 

  10. Paglia P et al. Gene transfer in dendritic cells, induced by oral DNA vaccination with Salmonella typhimurium, results in protective immunity against a murine fibrosarcoma Blood 1998 92: 3172–3176

    CAS  PubMed  Google Scholar 

  11. Jones BD, Falkow S . Salmonellosis: host immune responses and bacterial virulence determinants Annu Rev Immunol 1996 14: 533–561

    Article  CAS  PubMed  Google Scholar 

  12. Jane SM, Cunningham JM, Vanin EF . Vector development: a major obstacle in human gene therapy (editorial) Ann Med 1998 30: 413–415

    Article  CAS  PubMed  Google Scholar 

  13. Robbins PD, Ghivizzani SC . Viral vectors for gene therapy Pharmacol Ther 1998 80: 35–47

    Article  CAS  PubMed  Google Scholar 

  14. Michalski JC, Klein A . Glycoprotein lysosomal storage disorders: alpha- and beta-mannosidosis, fucosidosis and alpha-N-acetylgalactosaminidase deficiency Biochim Biophys Acta 1999 1455: 69–84

    Article  CAS  PubMed  Google Scholar 

  15. Feder JN . The hereditary hemochromatosis gene (HFE): a MHC class I-like gene that functions in the regulation of iron homeostasis Immunol Res 1999 20: 175–185

    Article  CAS  PubMed  Google Scholar 

  16. Nansen A et al. Role of interferon-gamma in the pathogenesis of LCMV-induced meningitis: unimpaired leucocyte recruitment, but deficient macrophage activation in interferon-gamma knock-out mice J Neuroimmunol 1998 86: 202–212

    Article  CAS  PubMed  Google Scholar 

  17. Kjerrulf M et al. Interferon-gamma receptor-deficient mice exhibit impaired gut mucosal immune responses but intact oral tolerance Immunology 1997 92: 60–68

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Montosi G et al. Wild type Hfe protein normalizes transferrin iron accumulation in macrophages from subjects with hereditary hemochromatosis Blood 2000 96: 1119–1124

    Google Scholar 

  19. Paglia P et al. The defined attenuated Listeria monocytogenes delta mp12 mutant is an effective oral vaccine carrier to trigger a long-lasting immune response against a mouse fibrosarcoma Eur J Immunol 1997 27: 1570–1575

    Article  CAS  PubMed  Google Scholar 

  20. Guzman CA et al. Attenuated Listeria monocytogenes carrier strains can deliver an HIV-1 gp120 T helper epitope to MHC class II-restricted human CD4+ T cells Eur J Immunol 1998 28: 1807–1814

    Article  CAS  PubMed  Google Scholar 

  21. Dietrich G et al. Delivery of DNA vaccines by attenuated intracellular bacteria Immunol Today 1999 20: 251–253

    Article  CAS  PubMed  Google Scholar 

  22. Dilts DA et al. Phase I clinical trials of aroA aroD and aroA aroD htrA attenuated S. typhi vaccines; effect of formulation on safety and immunogenicity Vaccine 2000 18: 1473–1484

    Article  CAS  PubMed  Google Scholar 

  23. Hone DM et al. A galE via (Vi antigen-negative) mutant of Salmonella typhi Ty2 retains virulence in humans Infect Immun 1988 56: 1326–1333

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Levine MM et al. Safety, infectivity, immunogenicity, and in vivo stability of two attenuated auxotrophic mutant strains of Salmonella typhi, 541Ty and 543Ty, as live oral vaccines in humans J Clin Invest 1987 79: 888–902

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Russell DW, Hirata RK . Human gene targeting by viral vectors Nat Genet 1998 18: 325–330

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Medina E et al. Pathogenicity island 2 mutants of Salmonella typhimurium are efficient carriers for heterologous antigens and enable modulation of immune responses Infect Immun 1999 67: 1093–1099

    CAS  PubMed  PubMed Central  Google Scholar 

  27. VanCott JL et al. Regulation of host immune responses by modification of Salmonella virulence genes Nature Med 1998 4: 1247–1252

    Article  CAS  PubMed  Google Scholar 

  28. Onodera M et al. Successful peripheral T-lymphocyte-directed gene transfer for a patient with severe combined immune deficiency caused by adenosine deaminase deficiency Blood 1998 91: 30–36

    CAS  PubMed  Google Scholar 

  29. Bordignon C et al. Gene therapy in peripheral blood lymphocytes and bone marrow for ADA-immunodeficient patients Science 1995 270: 470–475

    Article  CAS  PubMed  Google Scholar 

  30. Bordignon C et al. Cell therapy: achievements and perspectives Haematologica 1999 84: 1110–1149

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was in part supported by grants from Telethon-Italy (Grant Nos A102 and A135), ISS-AIDS-1998, AIRC, CNR (PF-Biotechnology), HGF-Strategiefondsprojekt 98/03 ‘Infektionsabwehr und Krebsprävention’ (P1.3) and the European Community (QLK2-CT-1999–00310).

Author information

Author notes

  1. N Terrazzini & K Schulze

    Present address: Department of Life Sciences, UEL, London, UK

Authors and Affiliations

  1. Immunotherapy and Gene Therapy Unit, Istituto Nazionale Tumori, Milano, Italy

    P Paglia, N Terrazzini & M P Colombo

  2. Division of Microbiology, Vaccine Research Group, GBF-German Research Centre for Biotechnology, Braunschweig, Germany

    C A Guzmán

Authors
  1. P Paglia
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. N Terrazzini
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. K Schulze
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. C A Guzmán
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. M P Colombo
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Paglia, P., Terrazzini, N., Schulze, K. et al. In vivo correction of genetic defects of monocyte/ macrophages using attenuated Salmonella as oral vectors for targeted gene delivery. Gene Ther 7, 1725–1730 (2000). https://doi.org/10.1038/sj.gt.3301290

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.gt.3301290

Keywords

This article is cited by

Search

Advanced search

Quick links