How kala-azar bug evades drugs
doi:10.1038/nindia.2013.19 Published online 5 February 2013
Researchers have got new insight into how the kala-azar bug Leishmania donovani manages to evade and gain resistance to a class of drugs called antimonials. Through intricate operations in its cell surface glycans – a covering of complex sugar molecules – the protozoan parasite triggers over expression of the Multidrug resistant protein 1 (MDR1), which kicks out the antimonial drugs from the host cell, according to the research.
The bug has re-emerged worldwide due to resistance to pentavalent antimonial drugs, which were introduced in the Indian subcontinent about nine decades ago with dramatic clinical success. Like other countries of the Indian subcontinent, India had to abandon the use of antimonials after the widespread emergence of parasites resistant to this class of drugs.
The researchers studied the parasite-host cell interaction on the cell surface of L. donovani which is covered with complex sugar molecules known as glycoconjugates or glycans. They explored the complex interaction between antimony resistant parasite surface glycoconjugates, infectivity and production of the protein Interleukin-10 (IL-10).
"Antimony resistant glycans induce the production of IL-10 from macrophages. This upregulates the expression of host MDR1 and might eventually contribute to drug resistance and increased pathogenicity," says co-author Syamal Roy. These findings broaden the view of molecular mechanisms involved in antimonial resistance and suggest that further studies on drug resistance should not only focus on the parasite, but also explore its direct interface, the macrophage, he adds.
The researchers say the study raises concern about the impact of major molecular adaptations on the outcome of the few available drugs that have been implemented to control kala-azar in the Indian Subcontinent.
The authors of this study are from: Infectious Disease and Immunology, CSIR-Indian Institute of Chemical Biology, Kolkata; Microbiology and Cell Biology, Indian Institute of Science, Bangalore and Institute of Medical Sciences, BHU, Varanasi, India; Department of Parasitology, Institute of Tropical Medicine, and Department of Biomedical Sciences, University of Antwerp, Belgium.
- Mukherjee, B. et al. Antimony-resistant but not antimony-sensitive Leishmania donovani up-regulates host IL-10 to overexpress multidrug-resistant protein 1. P. Natl. Acad. Sci. USA (2013) doi: 10.1073/pnas.1213839110