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A Defective Oxidative Burst and Impaired Antigen Presentation are Hallmarks of Human Visceral Leishmaniasis

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Abstract

Purpose

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.

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Acknowledgments

Financial assistance was provided by Indian Council for Medical Research (ICMR), Council for Scientific & Industrial Research (CSIR) and Department of Science and Technology (DST), Govt. of India. S.R. is recipient of a Senior Research fellowship from CSIR, D.M. and S.G. are recipients of a Senior Research fellowship from ICMR, Govt. of India while S.M. is a recipient of an INSPIRE-Senior Research fellowship from DST, Govt. of India.

Conflict of Interest

The authors report no conflict of interest and are responsible for the content and writing of the paper.

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Authors and Affiliations

  1. Department of Pharmacology, Institute of Post Graduate Medical Education and Research, 244 B, Acharya J C Bose Road, Kolkata, 700020, West Bengal, India

    Susmita Roy, Debanjan Mukhopadhyay, Shibabrata Mukherjee, Susmita Ghosh & Mitali Chatterjee

  2. Department of Tropical Medicine, School of Tropical Medicine, Kolkata, 700073, West Bengal, India

    Shishir Kumar, Kumkum Sarkar, Dipankar Pal, Pratik Bhowmik, Kausik Mandal, Dolanchampa Modak, Subhasish Kamal Guha, Netai Pramanik, Rama Prosad Goswami & Bibhuti Saha

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Correspondence to Mitali Chatterjee.

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Roy, S., Mukhopadhyay, D., Mukherjee, S. et al. A Defective Oxidative Burst and Impaired Antigen Presentation are Hallmarks of Human Visceral Leishmaniasis. J Clin Immunol 35, 56–67 (2015). https://doi.org/10.1007/s10875-014-0115-3

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  • DOI: https://doi.org/10.1007/s10875-014-0115-3

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