title: A Defective Oxidative Burst and Impaired Antigen Presentation are Hallmarks of Human Visceral Leishmaniasis.
abstract: OBJECTIVE
  Survival of the Leishmania parasite within monocytes hinges on its ability to effectively nullify their microbicidal effector mechanisms. Accordingly, this study aimed to delineate this biological niche in patients with visceral leishmaniasis (VL).
  
  
  METHODS
  In monocytes, the redox status, antigen presenting capacity, expression of Toll-like receptors (TLRs), co-stimulatory molecules (CD80/86) and generation of intracellular cytokines (IL-8, IL-1β, IL-10 and LAP-TGF-β1) was measured by flow cytometry, levels of circulating cytokines (IL-1β, IL-6, TNF-α, IL-8, IL-4, IL-13, IL-10 and GM-CSF) by ELISA and arginase activity by spectrophotometry.
  
  
  RESULTS
  Within monocytes, generation of an oxidative burst was markedly attenuated as evident by decreased generation of nitric oxide and reactive oxygen species, concomitant with raised levels of thiols. This was accompanied by lowered frequency of TLR4(+) monocytes, but the arginase activity remained unaltered. Pathogen persistence was enhanced by the predominance of anti-inflammatory cytokines within monocytes, notably IL-10. Alongside, development of adaptive immunity was severely attenuated as manifested by a pronounced impairment of antigen presentation and co-stimulation evident by down regulation of CD54, HLA-DR and CD86. Treatment corrected the redox imbalance and reversed the impaired antigen presentation.
  
  
  CONCLUSIONS
  In VL, monocyte functions were severely impaired facilitating parasite persistence; anti-leishmanial chemotherapy mediated parasite elimination through modulation of the macrophage microenvironment by restoring its redox status and antigen presenting capacity.
authors.affiliation: Department of Pharmacology, Institute of Post Graduate Medical Education and Research, 244 B, Acharya J C Bose Road, Kolkata, 700020, West Bengal, India.
authors.forename: Susmita
authors.initials: S
authors.lastname: Roy
authors.affiliation: Department of Pharmacology, Institute of Post Graduate Medical Education and Research, 244 B, Acharya J C Bose Road, Kolkata, 700020, West Bengal, India.
authors.forename: Debanjan
authors.initials: D
authors.lastname: Mukhopadhyay
authors.affiliation: Department of Pharmacology, Institute of Post Graduate Medical Education and Research, 244 B, Acharya J C Bose Road, Kolkata, 700020, West Bengal, India.
authors.forename: Shibabrata
authors.initials: S
authors.lastname: Mukherjee
authors.affiliation: Department of Pharmacology, Institute of Post Graduate Medical Education and Research, 244 B, Acharya J C Bose Road, Kolkata, 700020, West Bengal, India.
authors.forename: Susmita
authors.initials: S
authors.lastname: Ghosh
authors.affiliation: Department of Tropical Medicine, School of Tropical Medicine, Kolkata, 700073, West Bengal, India.
authors.forename: Shishir
authors.initials: S
authors.lastname: Kumar
authors.affiliation: Department of Tropical Medicine, School of Tropical Medicine, Kolkata, 700073, West Bengal, India.
authors.forename: Kumkum
authors.initials: K
authors.lastname: Sarkar
authors.affiliation: Department of Tropical Medicine, School of Tropical Medicine, Kolkata, 700073, West Bengal, India.
authors.forename: Dipankar
authors.initials: D
authors.lastname: Pal
authors.affiliation: Department of Tropical Medicine, School of Tropical Medicine, Kolkata, 700073, West Bengal, India.
authors.forename: Pratik
authors.initials: P
authors.lastname: Bhowmik
authors.affiliation: Department of Tropical Medicine, School of Tropical Medicine, Kolkata, 700073, West Bengal, India.
authors.forename: Kausik
authors.initials: K
authors.lastname: Mandal
authors.affiliation: Department of Tropical Medicine, School of Tropical Medicine, Kolkata, 700073, West Bengal, India.
authors.forename: Dolanchampa
authors.initials: D
authors.lastname: Modak
authors.affiliation: Department of Tropical Medicine, School of Tropical Medicine, Kolkata, 700073, West Bengal, India.
authors.forename: Subhasish Kamal
authors.initials: SK
authors.lastname: Guha
authors.affiliation: Department of Tropical Medicine, School of Tropical Medicine, Kolkata, 700073, West Bengal, India.
authors.forename: Netai
authors.initials: N
authors.lastname: Pramanik
authors.affiliation: Department of Tropical Medicine, School of Tropical Medicine, Kolkata, 700073, West Bengal, India.
authors.forename: Rama Prosad
authors.initials: RP
authors.lastname: Goswami
authors.affiliation: Department of Tropical Medicine, School of Tropical Medicine, Kolkata, 700073, West Bengal, India.
authors.forename: Bibhuti
authors.initials: B
authors.lastname: Saha
authors.affiliation: Department of Pharmacology, Institute of Post Graduate Medical Education and Research, 244 B, Acharya J C Bose Road, Kolkata, 700020, West Bengal, India. ilatim@vsnl.net.
authors.forename: Mitali
authors.initials: M
authors.lastname: Chatterjee
mesh_terms: D056704:Adaptive Immunity; D000328:Adult; D017951:Antigen Presentation; D000953:Antigens, Protozoan / Q000378:metabolism; D016022:Case-Control Studies; D016207:Cytokines / Q000378:metabolism; D005260:Female; D006790:Host-Parasite Interactions / Q000276:immunology; D006801:Humans; D007113:Immunity, Innate; D007891:Leishmania / Q000276:immunology / Q000472:pathogenicity; D007898:Leishmaniasis, Visceral / Q000276:immunology* / Q000378:metabolism* / Q000469:parasitology; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000276:immunology / Q000378:metabolism / Q000469:parasitology; D009569:Nitric Oxide / Q000378:metabolism; D016897:Respiratory Burst; D051193:Toll-Like Receptors / Q000378:metabolism; D055815:Young Adult
chemical_list: D000953:Antigens, Protozoan; D016207:Cytokines; D051193:Toll-Like Receptors; D009569:Nitric Oxide
keywords: Antigen presentation; Leishmania donovani; arginase; co-stimulation; nitric oxide; toll like receptors; visceral Leishmaniasis