The antidepressant sertraline provides a novel host directed therapy module for augmenting TB therapy

  1. Deepthi Shankaran
  2. Anjali Singh
  3. Stanzin Dawa
  4. Prabhakar Arumugam
  5. Sheetal Gandotra
  6. Vivek Rao  Is a corresponding author
  1. Institute of Genomics and Integrative Biology, India

Abstract

A prolonged therapy, primarily responsible for development of drug resistance by Mycobacterium tuberculosis (Mtb), obligates any new TB regimen to not only reduce treatment duration but also escape pathogen resistance mechanisms. With the aim of harnessing the host response in providing support to existing regimens, we used sertraline (SRT) to stunt the pro-pathogenic type I IFN response of macrophages to infection. While SRT alone could only arrest bacterial growth, it effectively escalated the bactericidal activities of Isoniazid (H) and Rifampicin (R) in macrophages. This strengthening of antibiotic potencies by SRT was more evident in conditions of ineffective control by these frontline TB drug, against tolerant strains or dormant Mtb. SRT, could significantly combine with standard TB drugs to enhance early pathogen clearance from tissues of mice infected with either drug sensitive/ tolerant strains of Mtb. Further, we demonstrate an enhanced protection in acute TB infection of the highly susceptible C3HeB/FeJ mice with the combination therapy signifying the use of SRT as a potent adjunct to standard TB therapeutic regimens against bacterial populations of diverse physiology. This study advocates a novel host directed adjunct therapy regimen for TB with a clinically approved anti-depressant to achieve quicker and greater control of infection.

Data availability

This manuscript does not include any sequencing or high through put data. Also this work does not include any protein crystallization and diffraction analysis. The manuscript does not involve data for submission to depositing datasets into a domain-specific public archive.

Article and author information

Author details

  1. Deepthi Shankaran

    Cardio Respiratory Disease Unit, Institute of Genomics and Integrative Biology, New Delhi, India
    Competing interests
    The authors declare that no competing interests exist.
  2. Anjali Singh

    Cardio Respiratory Disease Unit, Institute of Genomics and Integrative Biology, New Delhi, India
    Competing interests
    The authors declare that no competing interests exist.
  3. Stanzin Dawa

    Cardio Respiratory Disease Unit, Institute of Genomics and Integrative Biology, New Delhi, India
    Competing interests
    The authors declare that no competing interests exist.
  4. Prabhakar Arumugam

    Cardio Respiratory Disease Unit, Institute of Genomics and Integrative Biology, New Delhi, India
    Competing interests
    The authors declare that no competing interests exist.
  5. Sheetal Gandotra

    Cardio Respiratory Disease Unit, Institute of Genomics and Integrative Biology, New Delhi, India
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1204-7290
  6. Vivek Rao

    Cardio Respiratory Disease Unit, Institute of Genomics and Integrative Biology, New Delhi, India
    For correspondence
    vivek.rao@igib.in
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8646-6634

Funding

Council of Scientific and Industrial Research, India (BSC0123)

  • Vivek Rao

Council of Scientific and Industrial Research, India (OLP0136)

  • Vivek Rao

Indian Council of Medical Research (GAP0213)

  • Vivek Rao

Council of Scientific and Industrial Research, India (STS0016)

  • Vivek Rao

Council of Scientific and Industrial Research, India (MLP2106)

  • Vivek Rao

Council of Scientific and Industrial Research, India (MLP2012)

  • Vivek Rao

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations of the Control and Supervision of Experiments on Animals (CPCSEA). Experiments were conducted in line with approved protocols of the Institutional animal ethics committee, CSIR- IGIB (IGIB/IAEC/OCT2018/10, IGIB/IAEC/13/28/2020).

Human subjects: The study was conducted in strict accordance with recommendations of the National Ethical Guidelines for Biomedical and Health Research Involving Human Participants, Indian Council of Medical Research (ICMR), Government of India. The protocols followed were approved by the Institutional human ethics committee of IGIB, proposal no 10, 2016 and Ref no: CSIR-IGIB/IHEC/2017-18 Dt. 08.02.2018. Patient informed consent was obtained prior to commencing the work.

Reviewing Editor

  1. Bavesh D Kana, University of the Witwatersrand, South Africa

Publication history

  1. Received: November 12, 2020
  2. Accepted: January 11, 2023
  3. Accepted Manuscript published: January 11, 2023 (version 1)

Copyright

© 2023, Shankaran 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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  1. Deepthi Shankaran
  2. Anjali Singh
  3. Stanzin Dawa
  4. Prabhakar Arumugam
  5. Sheetal Gandotra
  6. Vivek Rao
(2023)
The antidepressant sertraline provides a novel host directed therapy module for augmenting TB therapy
eLife 12:e64834.
https://doi.org/10.7554/eLife.64834

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