Mycobacterium tuberculosis Methyltransferase Rv1515c Can Suppress Host Defense Mechanisms by Modulating Immune Functions Utilizing a Multipronged Mechanism
Mycobacterium tuberculosis (M. tb) gene Rv1515c encodes a conserved hypothetical protein exclusively present within organisms of MTB complex and absent in non-pathogenic mycobacteria. In silico analysis revealed that Rv1515c contain S-adenosylmethionine binding site and methyltransferase domain. The...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-06-01
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| Series: | Frontiers in Molecular Biosciences |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fmolb.2022.906387/full |
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| author | Anshu Rani Anshu Rani Anwar Alam Faraz Ahmad Manjunath P. Abhinav Saurabh Sheeba Zarin Dipendra Kumar Mitra Seyed E. Hasnain Seyed E. Hasnain Nasreen Z. Ehtesham |
| author_facet | Anshu Rani Anshu Rani Anwar Alam Faraz Ahmad Manjunath P. Abhinav Saurabh Sheeba Zarin Dipendra Kumar Mitra Seyed E. Hasnain Seyed E. Hasnain Nasreen Z. Ehtesham |
| author_sort | Anshu Rani |
| collection | DOAJ |
| description | Mycobacterium tuberculosis (M. tb) gene Rv1515c encodes a conserved hypothetical protein exclusively present within organisms of MTB complex and absent in non-pathogenic mycobacteria. In silico analysis revealed that Rv1515c contain S-adenosylmethionine binding site and methyltransferase domain. The DNA binding and DNA methyltransferase activity of Rv1515c was confirmed in vitro. Knock-in of Rv1515c in a model mycobacteria M. smegmatis (M. s_Rv1515c) resulted in remarkable physiological and morphological changes and conferred the recombinant strain with an ability to adapt to various stress conditions, including resistance to TB drugs. M. s_Rv1515c was phagocytosed at a greater rate and displayed extended intra-macrophage survival in vitro. Recombinant M. s_Rv1515c contributed to enhanced virulence by suppressing the host defense mechanisms including RNS and ROS production, and apoptotic clearance. M. s_Rv1515c, while suppressing the phagolysosomal maturation, modulated pro-inflammatory cytokine production and also inhibited antigen presentation by downregulating the expression of MHC-I/MHC-II and co-stimulatory signals CD80 and CD86. Mice infected with M. s_Rv1515c produced more Treg cells than vector control (M. s_Vc) and exhibited reduced effector T cell responses, along-with reduced expression of macrophage activation markers in the chronic phase of infection. M. s_Rv1515c was able to survive in the major organs of mice up to 7 weeks post-infection. These results indicate a crucial role of Rv1515c in M. tb pathogenesis. |
| first_indexed | 2024-04-13T19:18:14Z |
| format | Article |
| id | doaj.art-a83a1bcf54864040878b23dad5f090fb |
| institution | Directory Open Access Journal |
| issn | 2296-889X |
| language | English |
| last_indexed | 2024-04-13T19:18:14Z |
| publishDate | 2022-06-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Molecular Biosciences |
| spelling | doaj.art-a83a1bcf54864040878b23dad5f090fb2022-12-22T02:33:37ZengFrontiers Media S.A.Frontiers in Molecular Biosciences2296-889X2022-06-01910.3389/fmolb.2022.906387906387Mycobacterium tuberculosis Methyltransferase Rv1515c Can Suppress Host Defense Mechanisms by Modulating Immune Functions Utilizing a Multipronged MechanismAnshu Rani0Anshu Rani1Anwar Alam2Faraz Ahmad3Manjunath P.4Abhinav Saurabh5Sheeba Zarin6Dipendra Kumar Mitra7Seyed E. Hasnain8Seyed E. Hasnain9Nasreen Z. Ehtesham10Kusuma School of Biological Sciences, Indian Institute of Technology Delhi (IIT-D), New Delhi, IndiaICMR-National Institute of Pathology, Safdarjung Hospital Campus, New Delhi, IndiaICMR-National Institute of Pathology, Safdarjung Hospital Campus, New Delhi, IndiaICMR-National Institute of Pathology, Safdarjung Hospital Campus, New Delhi, IndiaICMR-National Institute of Pathology, Safdarjung Hospital Campus, New Delhi, IndiaDepartment of Transplant Immunology and Immunogenetics, All India Institute of Medical Sciences, New Delhi, IndiaICMR-National Institute of Pathology, Safdarjung Hospital Campus, New Delhi, IndiaDepartment of Transplant Immunology and Immunogenetics, All India Institute of Medical Sciences, New Delhi, IndiaDepartment of Biochemical Engineering and Biotechnology, Indian Institute of Technology Delhi (IIT-D), New Delhi, IndiaDepartment of Life Science, School of Basic Sciences and Research, Sharda University, Greater Noida, IndiaICMR-National Institute of Pathology, Safdarjung Hospital Campus, New Delhi, IndiaMycobacterium tuberculosis (M. tb) gene Rv1515c encodes a conserved hypothetical protein exclusively present within organisms of MTB complex and absent in non-pathogenic mycobacteria. In silico analysis revealed that Rv1515c contain S-adenosylmethionine binding site and methyltransferase domain. The DNA binding and DNA methyltransferase activity of Rv1515c was confirmed in vitro. Knock-in of Rv1515c in a model mycobacteria M. smegmatis (M. s_Rv1515c) resulted in remarkable physiological and morphological changes and conferred the recombinant strain with an ability to adapt to various stress conditions, including resistance to TB drugs. M. s_Rv1515c was phagocytosed at a greater rate and displayed extended intra-macrophage survival in vitro. Recombinant M. s_Rv1515c contributed to enhanced virulence by suppressing the host defense mechanisms including RNS and ROS production, and apoptotic clearance. M. s_Rv1515c, while suppressing the phagolysosomal maturation, modulated pro-inflammatory cytokine production and also inhibited antigen presentation by downregulating the expression of MHC-I/MHC-II and co-stimulatory signals CD80 and CD86. Mice infected with M. s_Rv1515c produced more Treg cells than vector control (M. s_Vc) and exhibited reduced effector T cell responses, along-with reduced expression of macrophage activation markers in the chronic phase of infection. M. s_Rv1515c was able to survive in the major organs of mice up to 7 weeks post-infection. These results indicate a crucial role of Rv1515c in M. tb pathogenesis.https://www.frontiersin.org/articles/10.3389/fmolb.2022.906387/fullmacrophagemulti drug resistancetuberculosistregspathogenicity |
| spellingShingle | Anshu Rani Anshu Rani Anwar Alam Faraz Ahmad Manjunath P. Abhinav Saurabh Sheeba Zarin Dipendra Kumar Mitra Seyed E. Hasnain Seyed E. Hasnain Nasreen Z. Ehtesham Mycobacterium tuberculosis Methyltransferase Rv1515c Can Suppress Host Defense Mechanisms by Modulating Immune Functions Utilizing a Multipronged Mechanism Frontiers in Molecular Biosciences macrophage multi drug resistance tuberculosis tregs pathogenicity |
| title | Mycobacterium tuberculosis Methyltransferase Rv1515c Can Suppress Host Defense Mechanisms by Modulating Immune Functions Utilizing a Multipronged Mechanism |
| title_full | Mycobacterium tuberculosis Methyltransferase Rv1515c Can Suppress Host Defense Mechanisms by Modulating Immune Functions Utilizing a Multipronged Mechanism |
| title_fullStr | Mycobacterium tuberculosis Methyltransferase Rv1515c Can Suppress Host Defense Mechanisms by Modulating Immune Functions Utilizing a Multipronged Mechanism |
| title_full_unstemmed | Mycobacterium tuberculosis Methyltransferase Rv1515c Can Suppress Host Defense Mechanisms by Modulating Immune Functions Utilizing a Multipronged Mechanism |
| title_short | Mycobacterium tuberculosis Methyltransferase Rv1515c Can Suppress Host Defense Mechanisms by Modulating Immune Functions Utilizing a Multipronged Mechanism |
| title_sort | mycobacterium tuberculosis methyltransferase rv1515c can suppress host defense mechanisms by modulating immune functions utilizing a multipronged mechanism |
| topic | macrophage multi drug resistance tuberculosis tregs pathogenicity |
| url | https://www.frontiersin.org/articles/10.3389/fmolb.2022.906387/full |
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