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Exopolyphosphatases PPX1 and PPX2 from Mycobacterium tuberculosis regulate dormancy response and pathogenesis
Prabhakar Tiwari1, Tannu Priya Gosain1, Saurabh Chugh1
1Infection and Immunology Group, Tuberculosis Research Laboratory, Translational Health Science and Technology Institute, Haryana, India.
Microbial Pathogenesis
|November 20, 2022
Summary
Enzymes regulating inorganic polyphosphate (PolyP) are crucial for Mycobacterium tuberculosis virulence and infection establishment. Targeting these PolyP homeostasis enzymes offers a promising strategy against drug-sensitive and drug-resistant tuberculosis.
Area of Science:
- Microbiology
- Molecular Biology
- Pathogenesis
Background:
- Stringent response pathways involving guanosine pentaphosphate and inorganic polyphosphate (PolyP) are vital for bacterial pathogen virulence.
- In Mycobacterium tuberculosis, polyphosphate kinase (PPK) and exopolyphosphatases (PPX) enzymes maintain intracellular PolyP levels.
Purpose of the Study:
- To investigate the role of M. tuberculosis exopolyphosphatases (PPX-1, PPX-2) in biofilm formation, survival, and infection.
- To elucidate the impact of PolyP homeostasis on the DosR regulon and host immune responses.
Main Methods:
- Generation and characterization of single (Δppx2) and double knockout (dkppx) M. tuberculosis strains.
- Infection models in guinea pigs and mice, transcriptional profiling (RNA-seq), and in vitro kinase assays.
- Host RNA-seq analysis of infected lung tissues.
Main Results:
- M. tuberculosis exopolyphosphatases are essential for biofilm formation, survival under nutrient limitation, and macrophage infection.
- M. tuberculosis dkppx strains exhibit reduced virulence and impaired infection establishment in vivo.
- PolyP inhibits DosT and DosS sensor kinase activity, and dkppx infection alters host antimicrobial gene expression.
Conclusions:
- Enzymes involved in PolyP homeostasis are critical for M. tuberculosis physiology and virulence.
- Targeting PolyP homeostasis enzymes represents a potential therapeutic strategy for tuberculosis, including drug-resistant strains.
Keywords:
Dormancy associated genesExopolyphosphatasesInorganic polyphosphate homeostasisMycobacterium tuberculosisVirulenceMore Related Videos
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