Mycobacterium tuberculosis exploits host ATM kinase for survival advantage through SecA2 secretome
Abstract
Mycobacterium tuberculosis (Mtb) produces inflections in the host signaling networks to create a favorable milieu for survival. The virulent Mtb strain, Rv caused double strand breaks (DSBs) whereas the non-virulent Ra strain triggered single stranded DNA generation. The effectors secreted by SecA2 pathway were essential and adequate for the genesis of DSBs. Accumulation of DSBs mediated through Rv activates ATM-Chk2 pathway of DNA damage response (DDR) signaling, resulting in altered cell cycle. Instead of the classical ATM-Chk2 DDR, Mtb gains survival advantage through ATM-Akt signaling cascade. Notably, in vivo infection with Mtb led to sustained DSBs and ATM activation during chronic phase of tuberculosis. Addition of ATM inhibitor enhances isoniazid mediated Mtb clearance in macrophages as well as in murine infection model, suggesting its utility for host directed adjunct therapy. Collectively, data suggests that DSBs inflicted by SecA2 secretome of Mtb provides survival niche through activation of ATM kinase.
Data availability
Numerical data for graphs is provided as a Source Data File.
Article and author information
Author details
Funding
Department of Biotechnology , Ministry of Science and Technology (BT/PR13522/COE/34/27/2015)
- Vinay Kumar Nandicoori
University Grants Commission (DS Kothari Postdoctoral Fellowship)
- Savita Lochab
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: The experimental protocol for the animal experiments was approved by the Animal Ethics Committee of the National Institute of Immunology, New Delhi, India. The approval (IAEC#409/16 & IAEC#462/18) is as per the guidelines issued by Committee for the Purpose of Control and Supervision of Experiments on Animals (CPCSEA), Government of India.
Reviewing Editor
- Bavesh D Kana, University of the Witwatersrand, South Africa
Publication history
- Received: August 29, 2019
- Accepted: March 27, 2020
- Accepted Manuscript published: March 30, 2020 (version 1)
- Version of Record published: April 16, 2020 (version 2)
- Version of Record updated: May 27, 2020 (version 3)
Copyright
© 2020, Lochab 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.
Metrics
-
- 2,201
- Page views
-
- 326
- Downloads
-
- 4
- Citations
Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.
Download links
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Further reading
-
- Genetics and Genomics
- Microbiology and Infectious Disease
Plasmids enable the dissemination of antimicrobial resistance (AMR) in common Enterobacterales pathogens, representing a major public health challenge. However, the extent of plasmid sharing and evolution between Enterobacterales causing human infections and other niches remains unclear, including the emergence of resistance plasmids. Dense, unselected sampling is highly relevant to developing our understanding of plasmid epidemiology and designing appropriate interventions to limit the emergence and dissemination of plasmid-associated AMR. We established a geographically and temporally restricted collection of human bloodstream infection (BSI)-associated, livestock-associated (cattle, pig, poultry, and sheep faeces, farm soils) and wastewater treatment work (WwTW)-associated (influent, effluent, waterways upstream/downstream of effluent outlets) Enterobacterales. Isolates were collected between 2008-2020 from sites <60km apart in Oxfordshire, UK. Pangenome analysis of plasmid clusters revealed shared 'backbones', with phylogenies suggesting an intertwined ecology where well-conserved plasmid backbones carry diverse accessory functions, including AMR genes. Many plasmid 'backbones' were seen across species and niches, raising the possibility that plasmid movement between these followed by rapid accessory gene change could be relatively common. Overall, the signature of identical plasmid sharing is likely to be a highly transient one, implying that plasmid movement might be occurring at greater rates than previously estimated, raising a challenge for future genomic One Health studies.
-
- Microbiology and Infectious Disease
A domain in the ORF1 polyprotein of the hepatitis E virus that was previously thought to be a protease is actually a zinc-binding domain.