Host Sirtuin 2 as an immunotherapeutic target against tuberculosis
- National Institute of Immunology, India
- International Centre for Genetic Engineering and Biotechnology, India
- Indian Institute of Science, India
Abstract
Mycobacterium tuberculosis (Mtb) employs plethora of mechanisms to hijack the host defence machinery for its successful survival, proliferation and persistence. Here we show that Mtb upregulates one of the key epigenetic modulators, NAD+ dependent histone deacetylase Sirtuin 2 (SIRT2), which upon infection translocate to the nucleus and deacetylates histone H3K18, thus modulating the host transcriptome leading to enhanced macrophage activation. Furthermore, in Mtb specific T cells, SIRT2 deacetylates NFκB-p65 at K310 to modulate T helper cell differentiation. Pharmacological inhibition of SIRT2 restricts the intracellular growth of both drug-sensitive and resistant strains of Mtb and enhances the efficacy of front line anti-TB drug Isoniazid in the murine model of infection. SIRT2 inhibitor-treated mice display reduced bacillary load, decreased disease pathology and increased Mtb specific protective immune responses. Overall, this study provides a link between Mtb infection, epigenetics and host immune response, which can be exploited to achieve therapeutic benefits.
Data availability
All data generated or analysed during this study are included in the manuscript. Source data files have been provided for all the Figures.
Article and author information
Author details
Ved Prakash Dwivedi
Vinay Kumar Nandicoori
Funding
Department of Science and Technology, Ministry of Science and Technology (NII/F-56/827/IFAD)
- Ashima Bhaskar
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: Animal experiments were carried out in accordance with the guidelines approved by the Animal Ethics Committee of National Institute of Immunology (NII, Approval ID: IAEC#409/16 & IAEC#462/18), New Delhi, India, International Centre for Genetic Engineering and Biotechnology (ICGEB, Approval ID: ICGEB/AH/2015/01/IMM-45), New Delhi, India and the Department of Biotechnology (DBT) Government of India. Mice were ethically sacrificed according to institutional and DBT regulations.
Copyright
© 2020, Bhaskar et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Host Sirtuin 2 as an immunotherapeutic target against tuberculosis
eLife 9:e55415.
https://doi.org/10.7554/eLife.55415
