1. Leishmania infection activates host mTOR for its survival by M2 macrophage polarization.
- Author
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Kumar A, Das S, Mandal A, Verma S, Abhishek K, Kumar A, Kumar V, Ghosh AK, and Das P
- Subjects
- Animals, Cell Polarity, Cell Survival, Female, Humans, Interleukin-12 genetics, Interleukin-12 immunology, Interleukin-1beta genetics, Interleukin-1beta immunology, Leishmania donovani immunology, Leishmania donovani physiology, Leishmaniasis genetics, Leishmaniasis parasitology, Leishmaniasis physiopathology, Mice, Mice, Inbred BALB C, NF-kappa B genetics, NF-kappa B immunology, Signal Transduction, TOR Serine-Threonine Kinases genetics, Tumor Necrosis Factor-alpha genetics, Tumor Necrosis Factor-alpha immunology, Leishmaniasis immunology, Macrophages cytology, Macrophages immunology, TOR Serine-Threonine Kinases immunology
- Abstract
Mammalian target of rapamycin (mTOR) is a central regulator of growth and immunity of host cells. It's involvement in cancer and tuberculosis is well documented but least explored in Leishmania donovani invasion of host cells. Therefore, in the present study, we aimed to investigate the role of mTOR in M2 macrophage polarization for Leishmania survival. We observed that Leishmania infection activated host mTOR pathway characterized by phosphorylation of mTOR, 70S6K and 4-EBP1. Inhibition of mTOR resulted in decreased parasite load and percent infectivity. Moreover, Leishmania infection triggered cell proliferation as was evidenced by increased expression of cyclin A and p-RPS6. mTOR activation during Leishmania infection resulted in reduced expression of M1 macrophage markers (eg, ROS, NO, iNOS, NOX-1, IL-12, IL-1β and TNF-α), and increased expression of M2 macrophage markers (eg, arginase-1, IL-10, TGF-β, CD206 and CD163). Furthermore, we observed that in case of Leishmania infection, mTOR inhibition increased the translocation of NF-κB to nucleus and deactivation of STAT-3. Eventually, we observed that inhibition of M2 macrophage polarization reduced Leishmania survival inside macrophages. Therefore, our findings suggest that mTOR plays a crucial role in regulation of M2 macrophage polarization and direct the innate immune homeostasis towards parasite survival inside host., (© 2018 John Wiley & Sons Ltd.)
- Published
- 2018
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