This article was co-authored by Dhwani Rupani, Dhruvika Chawalla and Vidhi Khanna
The antimony-resistant form of Leishmania donovani (LD), a protozoan parasite that causes “Kala Azar” has been found to show unique glycans, with N-acetylgalactosamine as the terminal residues, which leads to a surge of Interleukin-10 and in turn multi drug resistant protein (MDR) 1. Leishmaniasis is transmitted by the bite of phlebotomine sand flies and may be cutaneous, muco-cutaneous or visceral in nature. Visceral leishmaniasis, also known as Kala Azar, may be fatal if left untreated for over two years. Treatment involves the use of antimony compounds such as meglumine antimoniate and sodium stibogluconate. An increasing cause of concern for Kala Azar has been its re-emergence in recent times, attributed primarily to resistance of the parasite to antimonials. Mukherjee et al have highlighted that over expression of the N-acetylglycosamine glycoconjugates in amastigote as well as promastigote stages of antimony resistant LD have an important role to play in drug resistance.
The researchers traced the molecular mechanisms following infection of macrophages with antimony resistant LD (since protozoa entering the body are phagocytised by macrophages). They observed that antimony resistant LD acts via the toll-like receptors in our body. These toll-like receptors are proteins found on macrophages, responsible for regulating innate immune responses. Over activation of the toll like receptors by antimony resistant LD is followed by a number of intricate mechanisms eventually causing induction of Interleukin - 10 (IL-10). IL-10 is known to “deactivate” the infected macrophages, thus allowing disease progression. Apart from the action of antimony resistant LD on toll-like receptors, it also causes up regulation of the multi-drug resistant protein 1(MDR1). Up regulation of MDR1 takes place only in the presence of the IL-10 surge. MDR1 is an ATP dependant efflux pump that has been implicated in the resistance of a large number of chemotherapeutic drugs. MDR1 causes an efflux of antimony compounds from the macrophages, terminating their action and eventually causing resistance.
Considering that LD is a “master of manipulation of the host cell”; Mukherjee et al have performed laudable work by elucidating its evasive mechanisms of resistance. The researchers have compared experimental results from antimony resistant LD with antimony sensitive LD and knocked down antimony resistant LD. By this approach the possibility of any exogenous factors being involved in the development of resistance stands eliminated. Yet a few questions remain; in order to curtail the resistance mechanisms it is essential to decipher pathways involved (putative targets) and the role of the terminal N-acetylglycosylamines.
Leishmaniasis is an endemic disease found mainly in developing countries like India and Africa, where healthcare facilities are not up to the mark. Thus availability of effective drugs in such countries is a crucial deciding factor for the mortality rate. Recently, there has been an increase in the number of Leishmaniasis cases due to increasing resistance of the protozoan to first line agents i.e. the antimony compounds. Supplementary drugs may be used to combat the infection but do not give the success rate observed in case of antimony compounds, they can only enhance the effect of the first line agents. The research by Mukherjee and his team is a step towards re-enforcing the reign of antimony compounds in the treatment of Leishmaniasis. If it is possible to identify the susceptible steps of the resistance mechanisms it could be possible to modify the antimonials such that they remain unaffected by the “manipulation” of the protozoa or even identify novel agents for the treatment of this dreaded disease.
This is a companion discussion topic for the original entry at https://indiabioscience.org/news/2013/targeting-the-elusive-mechanisms-of-antimony-resistant-leishmania-donovani