Sodium stibogluconate resistance in Leishmania donovani correlates with greater tolerance to macrophage antileishmanial responses and trivalent antimony therapy.
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.
Carter
K C
KC
Department of Immunology, University of Strathclyde, Glasgow, UK. k.carter@strath.ac.uk
Hutchison
S
S
Boitelle
A
A
Murray
H W
HW
Sundar
S
S
Mullen
A B
AB
D000818:Animals; D000966:Antimony Potassium Tartrate / Q000494:pharmacology; D000967:Antimony Sodium Gluconate / Q000494:pharmacology* / Q000627:therapeutic use; D000981:Antiprotozoal Agents / Q000494:pharmacology* / Q000627:therapeutic use; D019328:Buthionine Sulfoximine / Q000494:pharmacology / Q000627:therapeutic use; D006224:Cricetinae; D004351:Drug Resistance; D005260:Female; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D015850:Interleukin-6 / Q000032:analysis / Q000096:biosynthesis; D007893:Leishmania donovani / Q000187:drug effects* / Q000276:immunology* / Q000472:pathogenicity; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology* / Q000469:parasitology; D008297:Male; D008647:Mesocricetus; D051379:Mice; D008807:Mice, Inbred BALB C; D009573:Nitrites / Q000032:analysis / Q000378:metabolism; D013154:Spleen / Q000737:chemistry / Q000469:parasitology; D014774:Virulence
D000981:Antiprotozoal Agents; D015850:Interleukin-6; D008070:Lipopolysaccharides; D009573:Nitrites; D019328:Buthionine Sulfoximine; D006861:Hydrogen Peroxide; D000966:Antimony Potassium Tartrate; D000967:Antimony Sodium Gluconate