Leishmania donovani, the causative agent of visceral leishmaniasis, infects and resides within tissue macrophage cells. It is not clear how the parasite infected cells crosstalk with the noninfected cells to regulate the infection process. During infection, Leishmania adopts a dual strategy for its survival by regulating the intercellular transport of host miRNAs to restrict inflammation. The parasite, by preventing mitochondrial function of host cells, restricts the entry of liver cell derived miR-122–containing extracellular vesicles in infected macrophages to curtail the inflammatory response associated with miR-122 entry. On contrary, the parasite up-regulates the export of miR-146a from the infected macrophages. The miR-146a, associated with the extracellular vesicles released by infected cells, restricts miR-122 production in hepatocytes while polarizing neighbouring naïve macrophages to the M2 state by affecting the cytokine expression. On entering the recipient macrophages, miR-146a dominates the miRNA antagonist RNA-binding protein HuR to inhibit the expression of proinflammatory cytokine mRNAs having HuR-interacting AU-rich elements whereas up-regulates anti-inflammatory IL-10 by exporting the miR-21 to polarize the recipient cells to M2 stage.
Leishmania donovani, the causative agent of visceral leishmaniasis, infects and resides within tissue macrophage cells of the mammalian host. It is not clear how the parasite infected cells cross-talk with the non-infected cells in the infection niche to regulate the infection process. Interestingly, miRNAs, the regulatory small RNAs of the host, could get trafficked into and out of infected cells as part of extracellular vesicles to ensure exchange of the epigenetic signals and can regulate the expression of their target genes in both donor and recipient cells. Leishmania, for its survival in host macrophage, adopts a dual strategy to regulate the intercellular transport of host miRNAs. The parasite, by preventing mitochondrial function of the host cells, restricts the entry of liver cell derived miR-122 containing extracellular vesicles in infected macrophage to curtail the inflammatory response by miR-122. The parasite reciprocally upregulates the extracellular export of anti-inflammatory miR-146a from the infected cells. The exported miR-146a restricts miR-122 production in liver cells and polarizes neighbouring naïve macrophages to the M2 state by targeting RNA Binder protein HuR.
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