Leishmania infection activates host mTOR for its survival by M2 macrophage polarization.

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.

• Authors: Ajay Kumar, Sushmita Das, Abhishek Mandal, Sudha Verma, Kumar Abhishek, Ashish Kumar, Vinod Kumar, Ayan Kumar Ghosh, Pradeep Das
• Journal: Parasite immunology (Parasite Immunol) Vol. 40 Issue 11 Pg. e12586 (Nov 2018) ISSN: 1365-3024 [Electronic] England
• PMID: 30187512 (Publication Type: Journal Article, Retracted Publication)
• Copyright: © 2018 John Wiley & Sons Ltd.

Chemical References

• Interleukin-1beta
• NF-kappa B
• Tumor Necrosis Factor-alpha
• Interleukin-12
• mTOR protein, mouse
• TOR Serine-Threonine Kinases

Topics

• Animals
• Cell Polarity
• Cell Survival
• Female
• Humans
• Interleukin-12 (genetics, immunology)
• Interleukin-1beta (genetics, immunology)
• Leishmania donovani (immunology, physiology)
• Leishmaniasis (genetics, immunology, parasitology, physiopathology)
• Macrophages (cytology, immunology)
• Mice
• Mice, Inbred BALB C
• NF-kappa B (genetics, immunology)
• Signal Transduction
• TOR Serine-Threonine Kinases (genetics, immunology)
• Tumor Necrosis Factor-alpha (genetics, immunology)