Leishmania survives by exporting miR-146a from infected to resident cells to subjugate inflammation

Abstract

Leishmania donovani, the causative agent of visceral leishmaniasis, infects and resides within tissuemacrophage 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 ofmiR-146a fromthe infected macrophages. The miR-146a, associated with the extracellular vesicles released by infected cells, restricts miR-122 production in hepatocytes while polarizing neighbouring naive 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 HuRinteracting AU-rich elements whereas up-regulates antiinflammatory IL-10 by exporting the miR-21 to polarize the recipient cells to M2 stage.