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Early CD44hiCD4+ and CD44hiCD8+ T cell numbers and the absence of mannose-rich glycoconjugates determine the protective outcome of anti-leishmanial immunity

Published online by Cambridge University Press:  02 June 2009

L. KEDZIERSKI ,
J. M. CURTIS  and
K. KEDZIERSKA
L. KEDZIERSKI*
Affiliation:
Infection and Immunity Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Australia
J. M. CURTIS
Affiliation:
Infection and Immunity Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Australia
K. KEDZIERSKA
Affiliation:
Department of Microbiology and Immunology, University of Melbourne, Parkville, Australia
*
*Corresponding author: Infection and Immunity Division, Walter and Eliza Hall Institute of Medical Research, 1G Royal Pde, Parkville3052, Australia. Tel: +61 3 93452475. Fax +61 3 93450852. E-mail: [email protected]
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Summary

Vaccination remains the best hope for control of all forms of leishmaniasis, and the development of a safe and effective vaccine is a critical global public-health priority. Our previous work showed that immunization with non-persistent phosphomannomutase-deficient (ΔPMM) Leishmania major parasites confers significant protection in susceptible BALB/c mice due to increased T-cell numbers and suppression of IL-10 and IL-13 early during infection. Here, we complemented the ΔPMM L. major parasites with human PMM2 to determine whether we could further improve the protection. Complemented ΔPMM parasites have restored glycoconjugate biosynthesis, while retaining avirulence of the parental knockout strain. Immunization with hPMM2 add-back parasites showed similar Th1/Th2 cytokine profiles to that observed in ΔPMM-vaccinated mice. However, the numbers of the activated CD4+CD44hi and CD8+CD44hi T cells recruited to the draining lymph nodes early after Leishmania infection were reduced, leading to decreased protection following hPMM2-immunization. Thus, the magnitude of T-cell responses early in the infection and the absence of mannose-rich glycoconjugates determine the protective outcome of anti-leishmanial immunity.

Keywords

Leishmaniavaccinephosphomannomutaseglycoconjugate
Type
Research Article
Information
Parasitology , Volume 136 , Issue 8 , July 2009 , pp. 833 - 840
Copyright
Copyright © Cambridge University Press 2009

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References

REFERENCES

Angeli, V., Ginhoux, F., Llodra, J., Quemeneur, L., Frenette, P. S., Skobe, M., Jessberger, R., Merad, M. and Randolph, G. J. (2006). B cell-driven lymphangiogenesis in inflamed lymph nodes enhances dendritic cell mobilization. Immunity 24, 203–215.CrossRefGoogle ScholarPubMed
Bogdan, C. and Rollinghoff, M. (1998). The immune response to Leishmania: mechanisms of parasite control and evasion. International Journal for Parasitology 28, 121–134.CrossRefGoogle ScholarPubMed
Fruth, U., Solioz, N. and Louis, J. A. (1993). Leishmania major interferes with antigen presentation by infected macrophages. Journal of Immunology 150, 1857–1864.CrossRefGoogle ScholarPubMed
Garami, A., Mehlert, A. and Ilg, T. (2001). Glycosylation defects and virulence phenotypes of Leishmania mexicana phosphomannomutase and dolicholphosphate-mannose synthase gene deletion mutants. Molecular and Cellular Biology 21, 8168–8183.CrossRefGoogle ScholarPubMed
Hsu, A. C. and Scott, P. (2007). Leishmania mexicana infection induces impaired lymph node expansion and Th1 cell differentiation despite normal T cell proliferation. Journal of Immunology 179, 8200–8207.CrossRefGoogle ScholarPubMed
Kaye, P. M., Rogers, N. J., Curry, A. J. and Scott, J. C. (1994). Deficient expression of co-stimulatory molecules on Leishmania-infected macrophages. European Journal of Immunology 24, 2850–2854.CrossRefGoogle ScholarPubMed
Kedzierski, L., Curtis, J. M., Doherty, P. C., Handman, E. and Kedzierska, K. (2008). Decreased IL-10 and IL-13 production and increased CD44(hi) T cell recruitment contribute to Leishmania major immunity induced by non-persistent parasites. European Journal of Immunology 38, 3090–3100.Google Scholar
Kedzierski, L., Malby, R. L., Smith, B. J., Perugini, M. A., Hodder, A. N., Ilg, T., Colman, P. M. and Handman, E. (2006 a). Structure of Leishmania mexicana phosphomannomutase highlights similarities with human isoforms. Journal of Molecular Biology 363, 215–227.Google Scholar
Kedzierski, L., Zhu, Y. and Handman, E. (2006 b). Leishmania vaccines: progress and problems. Parasitology 133 (Suppl.), S87–S112.CrossRefGoogle Scholar
Mitchell, G. F. (1983). Murine cutaneous leishmaniasis: resistance in reconstituted nude mice and several F1 hybrids infected with Leishmania tropica major. Journal of Immunogenetics 10, 395–412.CrossRefGoogle ScholarPubMed
Mitchell, G. F., Curtis, J. M., Handman, E. and McKenzie, I. F. (1980). Cutaneous leishmaniasis in mice: disease patterns in reconstituted nude mice of several genotypes infected with Leishmania tropica. Australian Journal of Experimental Biology and Medical Science 58, 521–532.CrossRefGoogle ScholarPubMed
Ponte-Sucre, A., Heise, D. and Moll, H. (2001). Leishmania major lipophosphoglycan modulates the phenotype and inhibits migration of murine Langerhans cells. Immunology 104, 462–467.Google Scholar
Spath, G. F., Lye, L. F., Segawa, H., Sacks, D. L., Turco, S. J. and Beverley, S. M. (2003). Persistence without pathology in phosphoglycan-deficient Leishmania major. Science 301, 1241–1243.CrossRefGoogle ScholarPubMed
Spath, G. F., Lye, L. F., Segawa, H., Turco, S. J. and Beverley, S. M. (2004). Identification of a compensatory mutant (lpg2-REV) of Leishmania major able to survive as amastigotes within macrophages without LPG2-dependent glycoconjugates and its significance to virulence and immunization strategies. Infection and Immunity 72, 3622–3627.CrossRefGoogle ScholarPubMed
Titus, R. G., Marchand, M., Boon, T. and Louis, J. A. (1985). A limiting dilution assay for quantifying Leishmania major in tissues of infected mice. Parasite Immunology 7, 545–555.Google Scholar
Turco, S. J. and Descoteaux, A. (1992). The lipophosphoglycan of Leishmania parasites. Annual Review of Microbiology 46, 65–94.CrossRefGoogle ScholarPubMed
Uzonna, J. E., Spath, G. F., Beverley, S. M. and Scott, P. (2004). Vaccination with phosphoglycan-deficient Leishmania major protects highly susceptible mice from virulent challenge without inducing a strong Th1 response. Journal of Immunology 172, 3793–3797.CrossRefGoogle ScholarPubMed
Uzonna, J. E., Wei, G., Yurkowski, D. and Bretscher, P. (2001). Immune elimination of Leishmania major in mice: implications for immune memory, vaccination, and reactivation disease. Journal of Immunology 167, 6967–6974.CrossRefGoogle ScholarPubMed
Webster, B., Ekland, E. H., Agle, L. M., Chyou, S., Ruggieri, R. and Lu, T. T. (2006). Regulation of lymph node vascular growth by dendritic cells. Journal of Experimental Medicine 203, 1903–1913.Google Scholar