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.
Highlights
Epigenetics encompasses any process that changes gene expression and is inherited without amending the fundamental DNA sequence [1]
The epigenetic states result in erratic gene expression profiles of host cells, which are responsible for warding off microbial infections [6, 7]
A recent study showed potential of miRNA-361-3p as a prognostic biomarker in cutaneous leishmaniasis (CL) caused by L. braziliensis [61]. miRNA-3613p expression was upregulated in patients with therapeutic failure to pentavalent antimony and required more healing times. miRNA-193b and−671 have been speculated to be prospective biosignatures for prognosis of localized cutaneous leishmaniasis (LCL) but require further validation [31]
Summary
Epigenetics encompasses any process that changes gene expression and is inherited without amending the fundamental DNA sequence [1]. The epigenetic states result in erratic gene expression profiles of host cells, which are responsible for warding off microbial infections [6, 7]. Leishmania secretes effector molecules to modulate host immune transcriptome resulting in alterations in the host epigenome, to alter cytokine and chemokine levels, their cross talks and downstream signaling hubs. This adversely affects the recruitment and activation of immune cells, respiratory burst and antigen presentation, leading to immune evasion [12]. Evolving evidence on the probable downstream effects of epigenetic regulation such as targeting epigenetic machinery to reset the waning immune response, via vaccine, or drug development and prognostic markers are discussed
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