Inorganic polyphosphate accumulation suppresses the dormancy response and virulence in Mycobacterium tuberculosis

Tiwari, Prabhakar and Gosain, Tannu Priya and Singh, Mamta and Sankhe, Gaurav D and Arora, Garima and Kidwai, Saqib and Agarwal, Sakshi and Chugh, Saurabh and Saini, Deepak K and Singh, Ramandeep (2019) Inorganic polyphosphate accumulation suppresses the dormancy response and virulence in Mycobacterium tuberculosis. In: JOURNAL OF BIOLOGICAL CHEMISTRY, 294 (28). pp. 10819-10832.

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Abstract

Stringent response pathways involving inorganic polyphosphate (PolyP) play an essential role in bacterial stress adaptation and virulence. The intracellular levels of PolyP are modulated by the activities of polyphosphate kinase-1 (PPK1), polyphosphate kinase-2 (PPK2), and exopolyphosphatases (PPXs). The genome of Mycobacterium tuberculosis encodes two functional PPXs, and simultaneous deletion of ppx1 and ppx2 results in a defect in biofilm formation. We demonstrate here that these PPXs cumulatively contribute to the ability of M. tuberculosis to survive in nutrient-limiting, low-oxygen growth conditions and also in macrophages. Characterization of single (Delta ppx2) and double knockout (dkppx) strains of M. tuberculosis indicated that PPX-mediated PolyP degradation is essential for establishing bacterial infection in guinea pigs. RNA-Seq-based transcriptional profiling revealed that relative to the parental strain, the expression levels of DosR regulon-regulated dormancy genes were significantly reduced in the dkppx mutant strain. In concordance, we also provide evidence that PolyP inhibits the autophosphorylation activities associated with DosT and DosS sensor kinases. The results in this study uncover that enzymes involved in PolyP homeostasis play a critical role in M. tuberculosis physiology and virulence and are attractive targets for developing more effective therapeutic interventions.

Item Type:	Journal Article
Publication:	JOURNAL OF BIOLOGICAL CHEMISTRY
Publisher:	AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
Additional Information:	Copyright of this article belongs to AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
Keywords:	microbiology; microbial pathogenesis; molecular biology; Mycobacterium tuberculosis; mycobacteria; inorganic polyphosphate homeostasis; virulence; exopolyphosphatases; dormancy-associated genes; biofilm; stress adaptation; bacterial pathogenesis; hypoxia
Department/Centre:	Division of Biological Sciences > Molecular Reproduction, Development & Genetics Division of Interdisciplinary Sciences > Centre for Biosystems Science and Engineering
Date Deposited:	20 Nov 2019 09:44
Last Modified:	20 Nov 2019 09:44
URI:	http://eprints.iisc.ac.in/id/eprint/63494

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