Abstract
Several intracellular pathogens arrest the phagosome maturation in the host cells to avoid transport to lysosomes. In contrast, the Leishmania containing parasitophorous vacuole (PV) is shown to recruit lysosomal markers and thus Leishmania is postulated to be residing in the phagolysosomes in macrophages. Here, we report that Leishmania donovani specifically upregulates the expression of Rab5a by degrading c-Jun via their metalloprotease gp63 to downregulate the expression of miR-494 in THP-1 differentiated human macrophages. Our results also show that miR-494 negatively regulates the expression of Rab5a in cells. Subsequently, L. donovani recruits and retains Rab5a and EEA1 on PV to reside in early endosomes and inhibits transport to lysosomes in human macrophages. Similarly, we have also observed that Leishmania PV also recruits Rab5a by upregulating its expression in human PBMC differentiated macrophages. However, the parasite modulates the endosome by recruiting Lamp1 and inactive pro-CathepsinD on PV via the overexpression of Rab5a in infected cells. Furthermore, siRNA knockdown of Rab5a or overexpression of miR-494 in human macrophages significantly inhibits the survival of the parasites. These results provide the first mechanistic insights of parasite-mediated remodeling of endo-lysosomal trafficking to reside in a specialized early endocytic compartment.
Highlights
Leishmania donovani (Ld) is an obligate intracellular parasite which causes visceral leishmaniasis in the mammalian hosts that affects annually about 12 million people worldwide [1]
We have found that Leishmania upregulates the expression of Rab5a, an early endosomal protein, by downregulating the expression of miR-494 in infected human macrophage as a consequence of gp63-dependent degradation of c-Jun
Parasites recruit and retain Rab5a and Early Endosome Associated Antigen (EEA1) on their parasitophorous vacuoles demonstrating that Leishmania resides in the early endosomal compartment and inhibits their transport to the lysosomes
Summary
Leishmania donovani (Ld) is an obligate intracellular parasite which causes visceral leishmaniasis in the mammalian hosts that affects annually about 12 million people worldwide [1]. This parasite is postulated to reside and replicate in a phagolysosomal compartment in mouse macrophages as the parasites acquire lysosomal markers such as Lysosome Associated Membrane Protein 1 (Lamp1), Lamp and CathepsinD on PV [2,3]. Some recent studies have shown that Leishmania modulates the recruitment of Rab7 [5] and ER markers [6] on PV in mouse macrophages. The Leishmania possibly resides in a hybrid compartment, but the nature of the compartment is not well characterized [7]
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