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Leishmania major H-line attenuated under pressure of gentamicin, induces a Th1 response which protects susceptible BALB/c mice against infection with virulent L. major

Published online by Cambridge University Press:  03 August 2009

HAMID DANESHVAR*
Affiliation:
Medical School, University of Kerman, Kerman, Iran
RICHARD BURCHMORE
Affiliation:
Sir Henry Wellcome Function Genomics Facility, Institute of Biomedical and Life Science, Joseph Black Building, University of Glasgow, Glasgow G12 8QQ, UK
PAUL HAGAN
Affiliation:
Division of Infection and Immunity, Glasgow Biomedical Research Centre, University of Glasgow, Glasgow G12 8TA, UK
R. STEPHEN PHILLIPS
Affiliation:
Division of Infection and Immunity, Glasgow Biomedical Research Centre, University of Glasgow, Glasgow G12 8TA, UK
*
*Corresponding author: Medical School, University of Kerman, Kerman, Iran. Tel: +98 341 2223016. Fax: +98 341 2112794. E-mail: hamiddaneshvar@hotmail.com

Summary

An attenuated line of Leishmania major (L. major H-line) has been established by culturing promastigotes in vitro under gentamicin pressure. A modification of the previously described method for the generation of attenuated L. major is described, giving rise to attenuated parasites after 8 rather than 12 subpassages. No lesions developed in BALB/c mice infected with L. major H-line, whereas L. major wild-type (WT) induced a Th2 like response with progressive lesions. Analysis of splenocyte IFN-γ and IL-4 production following stimulation with promastigotes shows that the L. major H-line preferentially induces Th1-like responses and possibly down-regulates Th2 responses in BALB/c mice. L. major H-line parasites remained localized in the skin and draining lymph node, whereas L. major WT parasites disseminated into the visceral organs of BALB/c mice. Mice infected with L. major H-line acquired some resistance against L. major WT. These results show that the attenuated cell line of L. major is not only avirulent but that it may also modulate the host immune response.

Type
Research Article
Copyright
Copyright © Cambridge University Press 2009

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References

REFERENCES

Constant, S., Pfeiffer, C., Woodard, A., Pasqualini, T. and Bottomly, K. (1995). Extent of T cell receptor ligation can determine the functional differentiation of naive CD4+ T cells. Journal of Experimental Medicine 182, 15911596.CrossRefGoogle ScholarPubMed
Daneshvar, H., Coombs, G. H., Hagan, P., Phillips, R. S. (2003 a). Leishmania mexicana and Leishmania major: attenuation of wild-type parasites and vaccination with the attenuated lines. Journal of Infectious Diseases 187, 16621668.CrossRefGoogle ScholarPubMed
Daneshvar, H., Hagan, P. and Phillips, R. S. (2003 b). Leishmania mexicana H-line attenuated under pressure of gentamicin, potentiates a Th1 response and control of cutaneous leishmaniasis in BALB/c mice. Parasite Immunology 25, 589596.CrossRefGoogle ScholarPubMed
Heinzel, F. P., Rerko, R. M., Ahmed, F. and Pearlman, E. (1995). Endogenous IL-12 is required for control of Th2 cytokine responses capable of exacerbating leishmaniasis in normally resistant mice. Journal of Immunology 155, 730739.CrossRefGoogle ScholarPubMed
Kopf, M., Brombacher, F., Köhler, G., Kienzle, G., Widmann, K. H., Lefrang, K., Humborg, C., Ledermann, B. and Solbach, W. (1996). IL-4-deficient Balb/c mice resist infection with Leishmania major. Journal of Exprimental Medicine 184, 11271136.Google ScholarPubMed
Kropf, P., Etges, R., Schopf, L., Chung, C., Sypek, J. and Muller, I. (1997). Characterization of T cell-mediated responses in nonhealing and healing Leishmania major infections in the absence of endogenous IL-4. Journal of Immunology 159, 34343443.CrossRefGoogle ScholarPubMed
Laskay, T., Diefenbach, A., Rollinghoff, M. and Solbach, W. (1995). Early parasite containment is decisive for resistance of Leishmania major infection. European Journal of Immunology 25, 22202231.CrossRefGoogle ScholarPubMed
Liew, F. Y. and O'Donnell, C. A. (1993). Immunology of leishmaniasis. Advances in Parasitology 32, 161259.CrossRefGoogle ScholarPubMed
Mottram, J. C., Souza, A. E., Hutchison, J. E., Cater, R., Frame, M. J. and Coombs, G. H. (1996). Evidence from disruption of the lmcp gene array of Leishmania mexicana that cysteine proteinases are virulence factors. Proceeding of the National Academy of Sciences, USA 93, 60086013.CrossRefGoogle Scholar
Nacy, C. A., Fortier, A. H., Meltzer, M. S., Buchmeier, N. A. and Schreiber, R. D. (1985). Macrophage activation to kill Leishmania major: activation of macrophages for intracellular destruction of amastigotes can be induced by both recombinant interferon-gamma and non-interferon lymphokines. Journal of Immunology 135, 35053511.CrossRefGoogle ScholarPubMed
Naderer, T., Ellis, M. A., Fleur Sernee, M. D. P., Curtis, J., Handman, E. and McConville, M. J. (2005). Virulence of Leishmania major in macrophages and mice requires the gluconeogenic enzyme fructose-1,6-bisphosphatase. Proceedings of the National Academy of Sciences, USA 103, 55025507.CrossRefGoogle Scholar
Oswald, I. P., Gazzinelli, R. T., Sher, A. and James, S. L. (1992). IL-10 synergizes with IL-4 and transforming transforming growth factor-beta to inhibit macrophage cytotoxic activity. Journal of Immunology 148, 35783582.CrossRefGoogle ScholarPubMed
Pearson, R. D. and Sousa, A. Q. (1996). Clinical spectrum of leishmaniasis. Clinical Infectious Disease 22, 113.CrossRefGoogle ScholarPubMed
Reiner, S. L. and Locksley, R. M. (1995). The regulation of immunity to Leishmania major. Annual Review of Immunology 13, 151177.CrossRefGoogle ScholarPubMed
Sadick, M. D., Heinzel, F. P., Holaday, B. J., Pu, R. T., Dawkins, R. S. and Locksley, R. M. (1990). Cure of murine leishmaniasis with anti-interleukin 4 monoclonal antibody. Evidence for a T cell-dependent, interferon-γ-independent mechanism. Journal of Experimental Medicine 171, 115127.CrossRefGoogle Scholar
Satoskar, A., Brombacher, F., Dai, W. J., McInnes, I., Liew, F. Y., Alexander, J. and Walker, W. (1997). SCID mice reconstituted with IL-4 deficient lymphocytes, but not immunocompetent lymphocytes, are resistant to cutaneous leishmaniasis. Journal of Immunology 159, 50055013.CrossRefGoogle Scholar
Scharton-Kersten, T. and Scott, P. (1995). The role of the innate immune response in Th1 cell development following Leishmania major infection. Journal of Leukocyte Biology 57, 515522.CrossRefGoogle ScholarPubMed
Scott, P., Natovitz, P., Coffman, R. L., Pearce, E. and Sher, A. (1988). Immunoregulation of cutaneous leishmaniasis T cell lines that transfer protective immunity or exacerbation belong to different T helper subsets and respond to distinct parasite antigens. Journal of Experimental Medicine 168, 16751843.CrossRefGoogle ScholarPubMed
Scott, P. (1991). IFN-γ modulates the early development of Th1 and Th2 responses in murine model of cutaneous leishmaniasis. Journal of Immunology 147, 31493155.CrossRefGoogle ScholarPubMed
Sjölander, A., Baldwin, T. M., Curtis, J. M. and Handman, E. (1998). Induction of a Th1 immune response and simultaneous lack of activation of a Th2 response are required for generation of immunity to leishmaniasis. Journal of Immunology 160, 39493957.CrossRefGoogle ScholarPubMed
Snapper, C. M. and Paul, W. E. (1987). B cell stimulatory factor-1 (interleukin 4) prepares resting murine B cells to secrete IgG1 upon subsequent stimulation with bacterial lipopolysaccharide. Journal of Immunology 139, 1017.CrossRefGoogle ScholarPubMed
Spath, G. F. and Beverley, S. M. (2001). A lipophosphoglycan-independent method for isolation of infective Leishmania metacyclic promastigotes by density gradient centrifugation. Experimental Parasitology 99, 97–103.CrossRefGoogle ScholarPubMed
World Health Organization (1999). Tropical Disease Research Progress 1997–98. UNDP/World Bank/WHO Special Programme for Research and Training in Tropical Diseases (TDR). WHO. Geneva, Switzerland.Google Scholar