Leishmania highjack host lipid body for its proliferation in macrophages by overexpressing host Rab18 and TRAPPC9 by downregulating miR-1914-3p expression.

Lipids stored in lipid-bodies (LBs) in host cells are potential sources of fatty acids for pathogens. However, the mechanism of recruitment of LBs from the host cells by pathogens to acquire fatty acids is not known. Here, we have found that Leishmania specifically upregulates the expression of host Rab18 and its GEF, TRAPPC9 by downregulating the expression of miR-1914-3p by reducing the level of Dicer in macrophages via their metalloprotease gp63. Our results also show that miR-1914-3p negatively regulates the expression of Rab18 and its GEF in cells. Subsequently, Leishmania containing parasitophorous vacuoles (Ld-PVs) recruit and retain host Rab18 and TRAPPC9. Leishmania infection also induces LB biogenesis in host cells and recruits LBs on Ld-PVs and acquires FLC₁₂-labeled fatty acids from LBs. Moreover, overexpression of miR-1914-3p in macrophages significantly inhibits the recruitment of LBs and thereby suppresses the multiplication of parasites in macrophages as parasites are unable to acquire fatty acids. These results demonstrate a novel mechanism how Leishmania acquire fatty acids from LBs for their growth in macrophages. Author summary: Leishmania donovani which causes fatal disease known as visceral leishmaniasis, is dependent on its host to scavenge fatty acids for its survival. But, how Leishmania get fatty acids from host macrophages is not known. Lipid bodies are unique organelles that contain neutral lipids and fatty acids, therefore, LBs in macrophages could be the potential source of fatty acids for parasites. We have found that Leishmania upregulate the expression of host Rab18 and its GEF by downregulating the expression of miR-1914-3p in infected macrophages via the Ld-gp63-mediated inhibition of dicer expression. As biogenesis of LBs is shown to be regulated by Rab18, we have found that Leishmania infection induces LB biogenesis in macrophages and subsequently recruits LBs along with Rab18 and its GEF on Leishmania containing parasitophorous vacuoles. Finally, parasites-containing vacuoles acquire FLC₁₂-labeled fatty acids from LBs to meet their nutritional requirement. We have also shown that overexpression of miR-1914-3p in macrophages significantly inhibits the recruitment of LBs and thereby suppresses the growth of parasites in macrophages as parasites are unable to acquire nutrients from LBs. These results demonstrate how Leishmania acquire nutrients like fatty acids from LBs for their proliferation in macrophages. [ABSTRACT FROM AUTHOR]