Parasitology



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


K. C. CARTER a1c1, S. HUTCHISON a1, A. BOITELLE a1, H. W. MURRAY a1a2, S. SUNDAR a3 and A. B. MULLEN a4
a1 Department of Immunology, University of Strathclyde, Glasgow, UK
a2 Department of Medicine, Weill Medical College of Cornell University, New York, USA
a3 Department of Medicine, Institute of Medical Sciences, Baranas Hindu University, Varansi, India
a4 Department Pharmaceutical Sciences, University of Strathclyde, Glasgow, UK

Article author query
carter kc   [PubMed][Google Scholar] 
hutchison s   [PubMed][Google Scholar] 
boitelle a   [PubMed][Google Scholar] 
murray hw   [PubMed][Google Scholar] 
sundar s   [PubMed][Google Scholar] 
mullen ab   [PubMed][Google Scholar] 

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.

(Received April 7 2005)
(Revised June 1 2005)
(Accepted June 9 2005)


Key Words: Leishmania donovani; sodium stibogluconate; glutathione; drug resistance.

Correspondence:
c1 Department of Immunology, SIBS, University of Strathclyde, 31 Taylor Street, Glasgow G4 0NR, UK. Tel: +44 0141 548 3823. Fax: +44 0141 548 3427. E-mail: k.carter@strath.ac.uk


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