Leishmania-Host Interactions-An Epigenetic Paradigm

Abstract

Leishmaniasis is one of the major neglected tropical diseases, for which no vaccines exist. Chemotherapy is hampered by limited efficacy coupled with development of resistance and other side effects. Leishmania parasites elude the host defensive mechanisms by modulating their surface proteins as well as dampening the host's immune responses. The parasites use the conventional RNA polymerases peculiarly under different environmental cues or pressures such as the host's milieu or the drugs. The mechanisms that restructure post-translational modifications are poorly understood but altered epigenetic histone modifications are believed to be instrumental in influencing the chromatin remodeling in the parasite. Interestingly, the parasite also modulates gene expression of the hosts, thereby hijacking or dampening the host immune response. Epigenetic factor such as DNA methylation of cytosine residues has been incriminated in silencing of macrophage-specific genes responsible for defense against these parasites. Although there is dearth of information regarding the epigenetic alterations-mediated pathogenesis in these parasites and the host, the unique epigenetic marks may represent targets for potential anti-leishmanial drug candidates. This review circumscribes the epigenetic changes during Leishmania infection, and the epigenetic modifications they enforce upon the host cells to ensure a safe haven. The non-coding micro RNAs as post-transcriptional regulators and correlates of wound healing and toll-like receptor signaling, as well as prognostic biomarkers of therapeutic failure and healing time are also explored. Finally, we highlight the recent advances on how the epigenetic perturbations may impact leishmaniasis vaccine development as biomarkers of safety and immunogenicity.

Keywords: DNA methylation/demethylation; biomarkers; epigenetics; histone modification; host-pathogen Interactions; leishmaniasis; non-coding RNA; therapeutics.

Figure 1

Schematic model of epigenetic regulation during Leishmania infection. Interplay of various factors involved in controlling gene expression at the transcriptional (DNA and histone modifications) and post-transcriptional level (non-coding RNAs) is depicted. CpG-rich regions of repressed genes are usually methylated, which in turn recruit chromatin modifiers to keep the genes in any of the three states, i.e., repressed, expressed, or poised. Heavily expressed genes show neither DNA methylation nor acetylated histones, while repressed genes tend to have both methylated DNA and histones, which inhibit the accessibility of polymerases, and other factors required for transcription. Base J, a DNA modification is crucial for transcriptional control in Leishmania species. Various non-coding RNAs arising mostly from UTRs act as regulatory elements in a feedback loop (13, 14). JBP, Base J binding protein; PGC, polycistronic gene cluster; cSSRs, convergent strand switch regions; dSSRs, divergent strand switch regions; DOT, disrupter of telomere; ac, acetylation; me, methylation; me2, dimethylation; me3, trimethylation; HAT, histone acetyl transferase; sno, small nucleolar; sn, small nuclear; pi-wi, piwi interacting; si, small interfering; mi, micro; lnc, long non-coding.