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Sodium stibogluconate resistance in Leishmania donovani correlates with greater tolerance to macrophage antileishmanial responses and trivalent antimony therapy

Published online by Cambridge University Press:  15 August 2005

K. C. CARTER
Affiliation:
Department of Immunology, University of Strathclyde, Glasgow, UK
S. HUTCHISON
Affiliation:
Department of Immunology, University of Strathclyde, Glasgow, UK
A. BOITELLE
Affiliation:
Department of Immunology, University of Strathclyde, Glasgow, UK
H. W. MURRAY
Affiliation:
Department of Immunology, University of Strathclyde, Glasgow, UK Department of Medicine, Weill Medical College of Cornell University, New York, USA
S. SUNDAR
Affiliation:
Department of Medicine, Institute of Medical Sciences, Baranas Hindu University, Varansi, India
A. B. MULLEN
Affiliation:
Department Pharmaceutical Sciences, University of Strathclyde, Glasgow, UK

Abstract

Co-treatment of mice infected with different strains of Leishmania donovani with a non-ionic surfactant vesicle formulation of buthionine sulfoximine (BSO-NIV), and sodium stibogluconate (SSG), did not alter indicators of Th1 or Th2 responses but did result in a significant strain-independent up-regulation of IL6 and nitrite levels by stimulated splenocytes from treated mice compared to controls. The efficacy of BSO-NIV/SSG treatment was dependent on the host being able to mount a respiratory burst indicating that macrophages are important in controlling the outcome of treatment. In vitro studies showed that SSG resistance was associated with a greater resistance to killing by activated macrophages, treatment with hydrogen peroxide or potassium antimony tartrate. Longitudinal studies showed that a SSG resistant (SSG-R) strain was more virulent than a SSG susceptible (SSG-S) strain, resulting in significantly higher parasite burdens by 4 months post-infection. These results indicate that SSG exposure may favour the emergence of more virulent strains.

Type
Research Article
Copyright
© 2005 Cambridge University Press

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References

REFERENCES

Bailey, H. H. ( 1998). L-S, R-buthionine sulfoximine: historical development and clinical issues. Chemico-Biological Interactions 111–112, 239254.CrossRefGoogle Scholar
Banduwardene, R, Mullen, A. B. and Carter, K. C. ( 1997). Immune responses of Leishmania donovani infected BALB/c mice following treatment with free and vesicular sodium stibogluconate formulations. International Journal of Immunopharmacology 19, 195203.CrossRefGoogle Scholar
Barr, S. D. and Gedamu, L. ( 2003). Role of peroxidoxins in Leishmania chagasi survival. Evidence of an enzymatic defense against nitrosative stress. Journal of Biological Chemistry 278, 1081610823.Google Scholar
Carter, K. C., Baillie, A. J., Alexander, J. and Dolan, T. F. ( 1988). The therapeutic effect of sodium stibogluconate in the BALB/c mice infected with L. donovani is organ dependent. 1988. Journal of Pharmacy and Pharmacology 40, 370373.Google Scholar
Carter, K. C., Mullen, A. B., Sundar, S. and Kenney, R. T. ( 2001). The efficacy of vesicular and free sodium stibogluconate formulations against clinical isolates of Leishmania donovani. Antimicrobrobial Agents and Chemotherapy 45, 355359.CrossRefGoogle Scholar
Carter, K. C., Sundar, S., Spickett, C., Pereira, O. C. and Mullen, A. B. ( 2003). The in vivo susceptibility of Leishmania donovani to sodium stibogluconate is drug specific and can be reversed by inhibiting glutathione biosynthesis. Antimicrobrobial Agents and Chemotherapy 47, 15291535.CrossRefGoogle Scholar
Croft, S. L. and Coombs, G. H. ( 2003). Leishmaniasis – current chemotherapy and recent advances in the search for novel drugs. Trends in Parasitology 19, 502508.CrossRefGoogle Scholar
Engwerda, C. R. and Kaye, P. M. ( 1999). Organ-specific immune responses associated with infectious disease. Immunology Today 2000 21, 7378.Google Scholar
Gebel, T. ( 1997). Arsenic and antimony: comparative approach on mechanistic toxicology. Chemico-biological Interactions 107, 131144.CrossRefGoogle Scholar
Goodwin, L. C. and Page, J. E. ( 1943). A study of the excretion of inorganic antimonials using a polarographic procedure. Biochemistry 22, 236240.Google Scholar
Goyal, N., Roy, U. and Rastogi, A. K. ( 1996). Relative resistance of promastigotes of a virulent and an avirulent strain of Leishmania donovani to hydrogen peroxide. Free Radical Biology and Medicine 21, 683689.CrossRefGoogle Scholar
Grondin, K., Haimeur, A., Mukhopadhyay, R., Rosen, B. P. and Ouellette, M. ( 1997). Co-amplification of the gamma-glutamylcysteine synthetase gene gsh1 and of the ABC transporter gene pgpA in arsenite-resistant Leishmania tarentolae. EMBO Journal 16, 30573065.CrossRefGoogle Scholar
Haddad, J. J. ( 2002). Oxygen-sensing mechanisms and the regulation of redox-responsive transcription factors in development and pathophysiology. Respiratory Research 3, 2653.CrossRefGoogle Scholar
Haddad, J. J., Saade, N. E. and Safieh-Garabedian, B. ( 2002). Redox regulation of TNF-alpha biosynthesis: augmentation by irreversible inhibition of gamma-glutamylcysteine synthetase and the involvement of an I kappaB-alpha/NF-kappaB-independent pathway in alveolar epithelial cells. Cell Signal 14, 211218.CrossRefGoogle Scholar
Haimeur, A. and Ouellette, M. ( 1998). Gene amplification in Leishmania tarentolae selected for resistance to sodium stibogluconate. Antimicrobial Agents and Chemotherapy 42, 16891694.Google Scholar
Kapoor, P., Sachdev, M. and Madhubala, R. ( 2000). Inhibition of glutathione synthesis as a chemotherapeutic strategy for leishmaniasis. Tropical Medicine and International Health 5, 438442.CrossRefGoogle Scholar
Legare, D., Papadoulou, B., Roy, G., Mukhopadhyay, R., Haimeur, A., Dey, S., Grondin, K., Brochu, C., Rosen, B. P. and Ouellette, M. ( 1997). Efflux systems and increased trypanothionine levels in arsenite-resistant Leishmania. Experimental Parasitology 87, 275282.CrossRefGoogle Scholar
Murata, Y., Shimamura, T. and Hamuro, J. ( 2002). The polarization of T(h)1/T(h)2 balance is dependent on the intracellular thiol redox status of macrophages due to the distinctive cytokine production. International Immunology 14, 201212.CrossRefGoogle Scholar
Murray, H. W. and Delph-Etienne, S. ( 2000). Roles of endogenous gamma interferon and macrophage microbicidal mechanisms in host response to chemotherapy in experimental visceral leishmaniasis. Infection and Immunity 68, 288293.CrossRefGoogle Scholar
Murray, H. W. and Nathan, C. F. ( 1999). Macrophage microbial mechanism in vivo: reactive nitrogen versus oxygen intermediates in the killing of intracellular visceral leishmaniasis. Journal of Experimental Medicine 189, 741746.CrossRefGoogle Scholar
Sereno, D., Cavaleyra, M., Zemzoumi, K., Maquaire, S., Ouaissi, A. and Lemesre, J. L. ( 1998). Axenically grown amastigotes of Leishmania infantum used as an in vitro model to investigate the pentavalent antimony mode of action. Antimicrobial Agents and Chemotherapy 42, 30973102.Google Scholar
Sudhandiran, G. and Shaha, C. ( 2003). Antimonial induced increase in intracellular Ca2+ through non-selective cation channels in the host and the parasite is responsible for apoptosis of intracellular Leishmania donovani amastigotes. Journal of Biological Chemistry 278, 2512025132.CrossRefGoogle Scholar
THE REGISTRY OF TOXIC EFFECTS OF CHEMICAL SUBSTANCES ( 2003). RTECS #: CC6825000, CAS #: 28300-74-5.
Wyllie, S., Cunningham, M. L. and Fairlamb, A. H. ( 2004). Dual action of antimonial drugs on thiol redox metabolism in the human pathogen Leishmania donovani. Journal of Biological Chemistry 279, 3992539932.CrossRefGoogle Scholar