Exopolyphosphatases PPX1 and PPX2 from Mycobacterium tuberculosis regulate dormancy response and pathogenesis. (December 2022)

• Record Type: Journal Article
• Authors: Tiwari, Prabhakar; Gosain, Tannu Priya; Chugh, Saurabh; Singh, Mamta; Sankhe, Gaurav D.; Arora, Garima; Kidwai, Saqib; Agarwal, Sakshi; Saini, Deepak K.; Singh, Ramandeep
• Is Part Of: Microbial pathogenesis. Volume 173(2022)Part B
• Publication Date: 2022-12
• Subjects: Mycobacterium tuberculosis -- Inorganic polyphosphate homeostasis -- Virulence -- Exopolyphosphatases -- Dormancy associated genes; PPX Exopolyphosphatase -- TB Tuberculosis -- CFU Colony forming units -- PolyP Inorganic polyphosphate; Pathogenic microorganisms -- Periodicals; Pathology, Molecular -- Periodicals; Communicable Diseases -- microbiology -- Periodicals; Communicable Diseases -- parasitology -- Periodicals; Micro-organismes pathogènes -- Périodiques; Pathologie moléculaire -- Périodiques; Electronic journals; 616.9041
• DOI: 10.1016/j.micpath.2022.105885
• Languages: English
• ISSNs: 0882-4010

Abstract

Abstract: Stress adaptation and virulence of various bacterial pathogens require stringent response pathways involving guanosine pentaphosphate and inorganic polyphosphate (PolyP). In M. tuberculosis, intracellular PolyP levels are maintained by the activities of polyphosphate kinase (PPK-1, PPK-2) and exopolyphosphatases (PPX-1, PPX-2). We demonstrate that these exopolyphosphatases cumulatively contribute to biofilm formation and survival of M. tuberculosis in nutrient limiting, low oxygen growth conditions and in macrophages. Characterization of single ( Δppx2 ) and double knock out strain ( dkppx ) of M. tuberculosis demonstrated that these exopolyphosphatases are essential for establishing infection in guinea pigs and mice. Transcriptional profiling revealed that relative to the parental strain the expression of genes belonging to DosR regulon were significantly reduced in mid-log phase cultures of dkppx strain. We also show that PolyP inhibited the autophosphorylation activities associated with DosT and DosS sensor kinases. Host RNA-seq analysis revealed that transcripts involved in various antimicrobial pathways such as apoptosis, autophagy, macrophage activation, calcium signalling, innate and T-cell response were differentially expressed in lung tissues of dkppx strain infected mice. Taken together, we demonstrate that enzymes involved in PolyP homeostasis play a critical role in physiology and virulence of M. tuberculosis . These enzymes are attractive targets for developing novel interventions that might be active against drug-sensitive and drug-resistant M. tuberculosis . Highlights: Deletion of exopolyphosphatases PPX1 and PPX2 impairs the ability of M. tuberculosis to form biofilms. Expopolyphosphatases contribute to survival of M. tuberculosis in nutrient limiting and low oxygen growth conditions. Inorganic polyphosphate inhibits autophosphorylation of DosT and DosS sensor kinases. Exopolyphosphatases PPX1 and PPX2 are required for M. tuberculosis to establish disease in guinea pigs and mice. The increased expression of various antimicrobial pathways in the lung tissues might be responsible for attenuation of the double mutant strain. Enzymes involved in PolyP homeostasis are attractive targets for developing novel interventions that might be active against M. tuberculosis.