Leishmania donovani Secretory Mevalonate Kinase Regulates Host Immune Response and Facilitates Phagocytosis
Summary StatementLeishmania secretes over 151 proteins during in vitro cultivation. Cellular functions of one such novel protein: mevalonate kinase is discussed here; signifying its importance in Leishmania infection.Visceral Leishmaniasis is a persistent infection, caused by Leishmania donovani in...
| Autori principali: | , , , , , , , , , , |
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| Natura: | Articolo |
| Lingua: | English |
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Frontiers Media S.A.
2021-04-01
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| Serie: | Frontiers in Cellular and Infection Microbiology |
| Soggetti: | |
| Accesso online: | https://www.frontiersin.org/articles/10.3389/fcimb.2021.641985/full |
| _version_ | 1831565184226820096 |
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| author | Tanvir Bamra Taj Shafi Sushmita Das Manjay Kumar Manas Ranjan Dikhit Ajay Kumar Ashish Kumar Kumar Abhishek Krishna Pandey Abhik Sen Pradeep Das |
| author_facet | Tanvir Bamra Taj Shafi Sushmita Das Manjay Kumar Manas Ranjan Dikhit Ajay Kumar Ashish Kumar Kumar Abhishek Krishna Pandey Abhik Sen Pradeep Das |
| author_sort | Tanvir Bamra |
| collection | DOAJ |
| description | Summary StatementLeishmania secretes over 151 proteins during in vitro cultivation. Cellular functions of one such novel protein: mevalonate kinase is discussed here; signifying its importance in Leishmania infection.Visceral Leishmaniasis is a persistent infection, caused by Leishmania donovani in Indian subcontinent. This persistence is partly due to phagocytosis and evasion of host immune response. The underlying mechanism involves secretory proteins of Leishmania parasite; however, related studies are meagre. We have identified a novel secretory Leishmania donovani glycoprotein, Mevalonate kinase (MVK), and shown its importance in parasite internalization and immuno-modulation. In our studies, MVK was found to be secreted maximum after 1 h temperature stress at 37°C. Its secretion was increased by 6.5-fold in phagolysosome-like condition (pH ~5.5, 37°C) than at pH ~7.4 and 25°C. Treatment with MVK modulated host immune system by inducing interleukin-10 and interleukin-4 secretion, suppressing host’s ability to kill the parasite. Peripheral blood mononuclear cell (PBMC)-derived macrophages infected with mevalonate kinase-overexpressing parasites showed an increase in intracellular parasite burden in comparison to infection with vector control parasites. Mechanism behind the increase in phagocytosis and immunosuppression was found to be phosphorylation of mitogen-activated protein (MAP) kinase pathway protein, Extracellular signal-regulated kinases-1/2, and actin scaffold protein, cortactin. Thus, we conclude that Leishmania donovani Mevalonate kinase aids in parasite engulfment and subvert the immune system by interfering with signal transduction pathways in host cells, which causes suppression of the protective response and facilitates their persistence in the host. Our work elucidates the involvement of Leishmania in the process of phagocytosis which is thought to be dependent largely on macrophages and contributes towards better understanding of host pathogen interactions. |
| first_indexed | 2024-12-17T11:23:09Z |
| format | Article |
| id | doaj.art-923fdf5e84694a8e9bb7a6112ae87b51 |
| institution | Directory Open Access Journal |
| issn | 2235-2988 |
| language | English |
| last_indexed | 2024-12-17T11:23:09Z |
| publishDate | 2021-04-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Cellular and Infection Microbiology |
| spelling | doaj.art-923fdf5e84694a8e9bb7a6112ae87b512022-12-21T21:51:08ZengFrontiers Media S.A.Frontiers in Cellular and Infection Microbiology2235-29882021-04-011110.3389/fcimb.2021.641985641985Leishmania donovani Secretory Mevalonate Kinase Regulates Host Immune Response and Facilitates PhagocytosisTanvir Bamra0Taj Shafi1Sushmita Das2Manjay Kumar3Manas Ranjan Dikhit4Ajay Kumar5Ashish Kumar6Kumar Abhishek7Krishna Pandey8Abhik Sen9Pradeep Das10Department of Molecular Biology, ICMR–Rajendra Memorial Research Institute of Medical Sciences, Patna, IndiaDepartment of Molecular Biology, ICMR–Rajendra Memorial Research Institute of Medical Sciences, Patna, IndiaDepartment of Microbiology, AIIMS, Patna, IndiaDepartment of Molecular Biology, ICMR–Rajendra Memorial Research Institute of Medical Sciences, Patna, IndiaDepartment of Molecular Biology, ICMR–Rajendra Memorial Research Institute of Medical Sciences, Patna, IndiaDepartment of Molecular Biology, ICMR–Rajendra Memorial Research Institute of Medical Sciences, Patna, IndiaDepartment of Molecular Biology, ICMR–Rajendra Memorial Research Institute of Medical Sciences, Patna, IndiaDepartment of Molecular Biology, ICMR–Rajendra Memorial Research Institute of Medical Sciences, Patna, IndiaDepartment of Molecular Biology, ICMR–Rajendra Memorial Research Institute of Medical Sciences, Patna, IndiaDepartment of Molecular Biology, ICMR–Rajendra Memorial Research Institute of Medical Sciences, Patna, IndiaDepartment of Molecular Biology, ICMR–Rajendra Memorial Research Institute of Medical Sciences, Patna, IndiaSummary StatementLeishmania secretes over 151 proteins during in vitro cultivation. Cellular functions of one such novel protein: mevalonate kinase is discussed here; signifying its importance in Leishmania infection.Visceral Leishmaniasis is a persistent infection, caused by Leishmania donovani in Indian subcontinent. This persistence is partly due to phagocytosis and evasion of host immune response. The underlying mechanism involves secretory proteins of Leishmania parasite; however, related studies are meagre. We have identified a novel secretory Leishmania donovani glycoprotein, Mevalonate kinase (MVK), and shown its importance in parasite internalization and immuno-modulation. In our studies, MVK was found to be secreted maximum after 1 h temperature stress at 37°C. Its secretion was increased by 6.5-fold in phagolysosome-like condition (pH ~5.5, 37°C) than at pH ~7.4 and 25°C. Treatment with MVK modulated host immune system by inducing interleukin-10 and interleukin-4 secretion, suppressing host’s ability to kill the parasite. Peripheral blood mononuclear cell (PBMC)-derived macrophages infected with mevalonate kinase-overexpressing parasites showed an increase in intracellular parasite burden in comparison to infection with vector control parasites. Mechanism behind the increase in phagocytosis and immunosuppression was found to be phosphorylation of mitogen-activated protein (MAP) kinase pathway protein, Extracellular signal-regulated kinases-1/2, and actin scaffold protein, cortactin. Thus, we conclude that Leishmania donovani Mevalonate kinase aids in parasite engulfment and subvert the immune system by interfering with signal transduction pathways in host cells, which causes suppression of the protective response and facilitates their persistence in the host. Our work elucidates the involvement of Leishmania in the process of phagocytosis which is thought to be dependent largely on macrophages and contributes towards better understanding of host pathogen interactions.https://www.frontiersin.org/articles/10.3389/fcimb.2021.641985/fullLeishmaniamevalonate kinaseimmune responsephosphorylationinfectionsecretion |
| spellingShingle | Tanvir Bamra Taj Shafi Sushmita Das Manjay Kumar Manas Ranjan Dikhit Ajay Kumar Ashish Kumar Kumar Abhishek Krishna Pandey Abhik Sen Pradeep Das Leishmania donovani Secretory Mevalonate Kinase Regulates Host Immune Response and Facilitates Phagocytosis Frontiers in Cellular and Infection Microbiology Leishmania mevalonate kinase immune response phosphorylation infection secretion |
| title | Leishmania donovani Secretory Mevalonate Kinase Regulates Host Immune Response and Facilitates Phagocytosis |
| title_full | Leishmania donovani Secretory Mevalonate Kinase Regulates Host Immune Response and Facilitates Phagocytosis |
| title_fullStr | Leishmania donovani Secretory Mevalonate Kinase Regulates Host Immune Response and Facilitates Phagocytosis |
| title_full_unstemmed | Leishmania donovani Secretory Mevalonate Kinase Regulates Host Immune Response and Facilitates Phagocytosis |
| title_short | Leishmania donovani Secretory Mevalonate Kinase Regulates Host Immune Response and Facilitates Phagocytosis |
| title_sort | leishmania donovani secretory mevalonate kinase regulates host immune response and facilitates phagocytosis |
| topic | Leishmania mevalonate kinase immune response phosphorylation infection secretion |
| url | https://www.frontiersin.org/articles/10.3389/fcimb.2021.641985/full |
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