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.

Molecular signatures of anthroponotic cutaneous leishmaniasis in the lesions of patients infected with Leishmania tropica

“…S2 a). It is known that epigenetic regulation of gene expression and DNA methylation play important roles in the function of macrophages, which in turn may impact the survival of Leishmania in macrophages 26 , 27 . Several enriched signal transduction pathways, including “signaling by nuclear receptors”, “WNT”, “GPCR”, “Notch pathways” and “RHO GTPase effectors” were shown to impact the cytoskeletal and membrane architecture of the host cells during parasite infection 39 – 42 .…”

“…Several enriched signal transduction pathways, including “signaling by nuclear receptors”, “WNT”, “GPCR”, “Notch pathways” and “RHO GTPase effectors” were shown to impact the cytoskeletal and membrane architecture of the host cells during parasite infection 39 – 42 . There is currently a dearth of knowledge regarding transcription and post-transcription modifications of host genes induced by the Leishmania species 26 .…”

“…The "gene expression pathway" includes several genes "RNA Polymerase I promoter clearance"/promoter opening/transcription", "RUNX1 regulates genes involved in megakaryocyte differentiation and platelet function", "RUNX1 regulates transcription of genes involved in differentiation of hematopoietic stem cells", "Gene silencing by RNA", and "Transcriptional regulation by small RNAs". These pathways could potentially contribute to parasite survival by host immune silencing mechanisms, non-coding RNAs network manipulation and transcriptional arrest of the protein coding genes in macrophages [25][26][27] . Further studies are however needed to pinpoint the function of these pathways in pathogenesis of, and immunity to, leishmaniasis.…”

Unraveling the Role of Immune Checkpoints in Leishmaniasis

“…Immunity against Leishmania is complex and depends on many factors, such as genetic diversity, parasite species and isolates (27)(28)(29). Leishmania spp.…”

Combined therapy with adipose tissue-derived mesenchymal stromal cells and meglumine antimoniate controls lesion development and parasite load in murine cutaneous leishmaniasis caused by Leishmania amazonensis

“…Leishmaniasis is one of the most important neglected tropical diseases, ranking second in the number of deaths among parasitic diseases, surpassed only by malaria [ 1 ]. In Brazil, Leishmania ( Leishmania ) amazonensis is one of the main etiological agents of leishmaniasis.…”