title: Leishmania panamensis infection and antimonial drugs modulate expression of macrophage drug transporters and metabolizing enzymes: impact on intracellular parasite survival.
abstract: OBJECTIVE
  Treatment failure is multifactorial. Despite the importance of host cell drug transporters and metabolizing enzymes in the accumulation, distribution and metabolism of drugs targeting intracellular pathogens, their impact on the efficacy of antileishmanials is unknown. We examined the contribution of pharmacologically relevant determinants in human macrophages in the antimony-mediated killing of intracellular Leishmania panamensis and its relationship with the outcome of treatment with meglumine antimoniate.
  
  
  METHODS
  Patients with cutaneous leishmaniasis who failed (n = 8) or responded (n =8) to treatment were recruited. Gene expression profiling of pharmacological determinants in primary macrophages was evaluated by quantitative RT-PCR and correlated to the drug-mediated intracellular parasite killing. Functional validation was conducted through short hairpin RNA gene knockdown.
  
  
  RESULTS
  Survival of L. panamensis after exposure to antimonials was significantly higher in macrophages from patients who failed treatment. Sixteen macrophage drug-response genes were modulated by infection and exposure to meglumine antimoniate. Correlation analyses of gene expression and intracellular parasite survival revealed the involvement of host cell metallothionein-2A and ABCB6 in the survival of Leishmania during exposure to antimonials. ABCB6 was functionally validated as a transporter of antimonial compounds localized in both the cell and phagolysosomal membranes of macrophages, revealing a novel mechanism of host cell-mediated regulation of intracellular drug exposure and parasite survival within phagocytes.
  
  
  CONCLUSIONS
  These results provide insight into host cell mechanisms regulating the intracellular exposure of Leishmania to antimonials and variations among individuals that impact parasite survival. Understanding of host cell determinants of intracellular pharmacokinetics/pharmacodynamics opens new avenues to improved drug efficacy for intracellular pathogens.
authors: Centro Internacional de Entrenamiento e Investigaciones Médicas (CIDEIM), Carrera 125 No. 19-225 Cali, Colombia.
authors: Maria Adelaida
authors: MA
authors: Gómez
authors: Adriana
authors: A
authors: Navas
authors: Ricardo
authors: R
authors: Márquez
authors: Laura Jimena
authors: LJ
authors: Rojas
authors: Deninson Alejandro
authors: DA
authors: Vargas
authors: Victor Manuel
authors: VM
authors: Blanco
authors: Roni
authors: R
authors: Koren
authors: Dan
authors: D
authors: Zilberstein
authors: Nancy Gore
authors: NG
authors: Saravia
mesh_terms: D000328:Adult; D000981:Antiprotozoal Agents / Q000494:pharmacology / Q000627:therapeutic use*; D002470:Cell Survival; D005260:Female; D020869:Gene Expression Profiling; D054884:Host-Pathogen Interactions; D006801:Humans; D007891:Leishmania / Q000187:drug effects / Q000276:immunology* / Q000502:physiology*; D008264:Macrophages / Q000187:drug effects* / Q000469:parasitology*; D008297:Male; D008536:Meglumine / Q000494:pharmacology / Q000627:therapeutic use*; D000077485:Meglumine Antimoniate; D026901:Membrane Transport Proteins / Q000096:biosynthesis / Q000235:genetics; D008875:Middle Aged; D009942:Organometallic Compounds / Q000494:pharmacology / Q000627:therapeutic use*; D055815:Young Adult
chemical_list: D000981:Antiprotozoal Agents; D026901:Membrane Transport Proteins; D009942:Organometallic Compounds; D008536:Meglumine; D000077485:Meglumine Antimoniate
keywords: ABCB6; MT2A; host–pathogen interactions; leishmaniasis; phagolysosomes
references: Antimicrob Agents Chemother. 2008 Feb;52(2):526-33
references: 18070969
references: Biochemistry. 2007 Aug 21;46(33):9443-52
references: 17661442
references: Cell. 2006 Mar 24;124(6):1283-98
references: 16564017
references: J Antimicrob Chemother. 2004 Dec;54(6):982-90
references: 15537695
references: J Clin Microbiol. 2012 Jul;50(7):2207-11
references: 22518860
references: J Biol Chem. 2010 Jul 16;285(29):22244-53
references: 20463017
references: Am J Physiol Cell Physiol. 2008 Feb;294(2):C579-90
references: 18160489
references: J Infect Dis. 2000 Nov;182(5):1497-502
references: 11023473
references: J Biol Chem. 2005 Nov 11;280(45):37423-9
references: 16144837
references: Antimicrob Agents Chemother. 2010 Jun;54(6):2549-59
references: 20385852
references: Blood. 2003 Jul 15;102(2):672-81
references: 12663451
references: Biochem Biophys Res Commun. 2004 Sep 24;322(3):836-41
references: 15336539
references: Chem Biol Interact. 1992 Dec;85(2-3):127-40
references: 1493605
references: Infect Immun. 2008 Mar;76(3):1186-92
references: 18086813
references: PLoS One. 2012;7(2):e31752
references: 22359626
references: Toxicol Sci. 2011 Apr;120(2):519-28
references: 21266531
references: Biometals. 2003 Sep;16(3):441-6
references: 12680707
references: Nucleic Acids Res. 2007;35(7):2107-15
references: 17389644
references: Mol Biochem Parasitol. 2000 Oct;110(2):195-206
references: 11071276
references: J Antimicrob Chemother. 2003 May;51(5):1067-77
references: 12697641
references: Infect Immun. 2000 Jan;68(1):288-93
references: 10603400
references: J Parasitol. 1999 Apr;85(2):360-6
references: 10219320
references: Clin Microbiol Rev. 2008 Apr;21(2):334-59, table of contents
references: 18400800
references: Am J Trop Med Hyg. 1990 Nov;43(5):464-80
references: 2173431
references: Biometals. 2010 Oct;23(5):897-926
references: 20549307
references: PLoS One. 2012;7(5):e37378
references: 22655043
references: J Infect Dis. 2006 May 15;193(10):1375-83
references: 16619185
references: Antimicrob Agents Chemother. 2008 Mar;52(3):1080-93
references: 18056276
references: Infect Immun. 2000 Nov;68(11):6289-93
references: 11035737
references: J Infect Dis. 2010 Aug 15;202(3):406-15
references: 20583921
references: J Infect Dis. 2007 Feb 15;195(4):602-8
references: 17230422
references: Infect Immun. 2002 Dec;70(12):6734-40
references: 12438348
references: Nat Rev Microbiol. 2011 Jul 11;9(8):604-15
references: 21747391
references: Mol Cell Proteomics. 2011 Apr;10(4):M110.006403
references: 21252268
references: J Antimicrob Chemother. 2003 May;51(5):1055-65
references: 12697642
references: Toxicology. 2000 Jul 5;147(3):157-66
references: 10924798
references: Toxicol Sci. 2000 Jun;55(2):460-7
references: 10828279
references: Nature. 2006 Oct 5;443(7111):586-9
references: 17006453