ABSTRACT
Concerns regarding toxicity and resistance of current drugs in visceral leishmaniasis have been reported. Antimicrobial peptides are considered to be promising candidates and among them human cathelicidin hCAP18/LL-37 showed significant parasite killing on drug-sensitive and resistant Leishmania promastigotes, in addition to its apoptosis-inducing role. Administration of hCAP18/LL-37 to infected macrophages also decreased parasite survival and increased the host favorable cytokine interleukin 12. However, 1,25-dihydroxyvitamin D3 (vitamin D3)-induced endogenous hCAP18/LL-37 production was hampered in infected THP-1 cells. Infection also suppressed the vitamin D3 receptor (VDR), transcription factor of hCAP18/LL-37. cAMP response element modulator (CREM), the repressor of VDR, was induced in infection, resulting in suppression of both VDR and cathelicidin expression. PGE2/cAMP/PKA axis was found to regulate CREM induction during infection and silencing CREM in infected cells and BALB/c mice led to decreased parasite survival. This study documents the antileishmanial potential of cathelicidin and further identifies CREM as a repressor of cathelicidin in Leishmania infection.
Subject(s)
Antimicrobial Cationic Peptides , Cathelicidins , Cyclic AMP Response Element Modulator , Leishmania donovani , Leishmaniasis, Visceral , Macrophages , Mice, Inbred BALB C , Leishmania donovani/drug effects , Animals , Antimicrobial Cationic Peptides/metabolism , Antimicrobial Cationic Peptides/pharmacology , Humans , Leishmaniasis, Visceral/parasitology , Leishmaniasis, Visceral/drug therapy , Mice , Macrophages/parasitology , Macrophages/metabolism , THP-1 Cells , Cyclic AMP Response Element Modulator/metabolism , Cyclic AMP Response Element Modulator/genetics , Receptors, Calcitriol/metabolism , Receptors, Calcitriol/genetics , Antiprotozoal Agents/pharmacology , FemaleABSTRACT
Circular RNA (circRNA), a relatively new member of the non-coding RNA family, has spurred great interest among researchers following its discovery as a ubiquitous class within the RNA world. Rapid progress in circRNA biology has coincided with its identification in a plethora of diverse roles including regulation of gene expression and probable coding potential, as well as competing interactions with proteins and microRNAs in various pathological conditions. Emerging evidence suggests that circRNAs also function in viral infections. The deregulation of circRNAs during viral infection has prompted investigations into the possibilities of circRNA as a competing endogenous RNA (ceRNA) that modulates response to infection. Recently, viruses have been shown to encode circRNAs with proviral functions, providing a strong impetus for focused efforts to elucidate the networks coaxed by circRNAs during infection. This review elaborates on recent insights gained on the roles of circRNAs during virus infection and immunity.