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Abstract
Promastigote form of Leishmania, an intracellular pathogen, delays phagosome maturation and resides inside macrophages. But till date limited study has been done to manipulate the phagosomal machinery of macrophages to restrict Leishmania growth. Attenuated Leishmania strain exposed RAW 264.7 cells showed a respiratory burst and enhanced production of pro-inflammatory mediators. The augmentation of pro-inflammatory activity is mostly attributed to p38 MAPK and p44/42 MAPK. In our study, these activated macrophages are found to induce phagosome maturation when infected with pathogenic Leishmania donovani. Increased co-localization of carboxyfluorescein succinimidyl ester labeled pathogenic L. donovani with Lysosome was found. Moreover, increased co-localization was observed between pathogenic L. donovani and late phagosomal markers viz. Rab7, Lysosomal Associated Membrane Protein 1, Cathepsin D, Rab9, and V-ATPase which indicate phagosome maturation. It was also observed that inhibition of V-type ATPase caused significant hindrance in attenuated Leishmania induced phagosome maturation. Finally, it was confirmed that p38 MAPK is the key player in acidification and maturation of phagosome in attenuated Leishmania strain pre-exposed macrophages. To our knowledge, this study for the first time reported an approach to induce phagosome maturation in L. donovani infected macrophages which could potentiate short-term prophylactic response in future.
Highlights
The protozoan parasite Leishmania infects phagocytes causing a spectrum of diseases from less severe cutaneous leishmaniasis to lethal visceral leishmaniasis (VL)
It has been reported that activation of the p-44/42 Mitogen Activated Protein Kinases (MAPK) leads to induction of IL-10, while downregulation of p38 MAPK is responsible for abrogated IL-12 production[12,13]
Attenuated Leishmania Strain (ALS) is reported to be deficient of LPG24 which is important because LPG defective mutant show extensive phagosome maturation[15] and we observed that ALS pre-treated MΦ s showed increased phago-lysosome fusion when infected with Pathogenic L. donovani (PLD)
Summary
The protozoan parasite Leishmania infects phagocytes causing a spectrum of diseases from less severe cutaneous leishmaniasis to lethal visceral leishmaniasis (VL). Resolution of infection depends in eluding the effector arms and inducing anti-inflammatory cytokines like IL-10, TGF-β , and IL-4 as reviewed by Bhardwaj et al.[10] To create this favorable niche for Leishmania, Mitogen Activated Protein Kinases (MAPK) plays a critical role[11]. Co-infection of Leishmania with Plasmodium shows better Th1 response and lower Plasmodium survival[21] In another case of C. burnetti infection, there was less invasion of trypomastigotes, while increasing the vacuolar pH using bafilomycin caused greater invasion, suggesting that acidification of C. burnetti vacuoles plays the trick[22]. ALS pre-exposed MΦ s showed altered response upon infection with PLD. ALS is reported to be deficient of LPG24 which is important because LPG defective mutant show extensive phagosome maturation[15] and we observed that ALS pre-treated MΦ s showed increased phago-lysosome fusion when infected with PLD. In depth study confirm p38 MAPK as the key player in MΦ s activation as well as phagosomal maturation event in ALS pre-exposed MΦ s
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