Inorganic polyphosphate accumulation suppresses the dormancy response and virulence in Mycobacterium tuberculosis
Authors: Ramandeep Singh
Gaurav D Sankhe
Deepak K Saini
Prabhakar Tiwari
Tannu Priya Gosain
Saqib Kidwai
Sakshi Agarwal
Saurabh Chugh
Garima Arora
Mamta Singh
Journal: Journal of Biological Chemistry (2019)
Discipline: BIOLOGY & BIOCHEMISTRY
Keywords: Mycobacterium tuberculosis; bacterial pathogenesis; biofilm; dormancy-associated genes; exopolyphosphatases
Affiliations: From the Tuberculosis Research Laboratory, Vaccine and Infectious Disease Research Centre, Translational Health Science and Technology Institute, Haryana 121001, India and., the Centre for BioSystems Science and Engineering and., Department of Molecular Reproduction, Development, and Genetics, Biological Sciences Building, Indian Institute of Science, Bangalore, Karnataka 560012, India., From the Tuberculosis Research Laboratory, Vaccine and Infectious Disease Research Centre, Translational Health Science and Technology Institute, Haryana 121001, India and .

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 (Δppx2) 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. 

Retracted: Yes

PubPeer comments:
 In Tiwari et al., 2015, the wild type well is rigorously identical to the wt well from Arora et al., 2018 while the mazF396 well is rigorously identical to the ppx1 well from Tiwari et al., 2019 ![file] , 
 The wild type histology slides from Arora et al., 2018 look identical to the ones from Tiwari et al., 2019. Were controls using wild type materials actually performed for both of these experiments ? ![file] , 
 Thank you for bringing this to our attention. We are in touch with the Editorial Board of the Journal to address this matter. , 
 2020 retraction. https: www.jbc.org content 295 43 14791 VOLUME 294 (2019) PAGES 10819u201310832 The article has been withdrawn by the authors. Issues related to WT panels were identified. The image from the WT biofilm formation panel published in Agarwal, S., et al. (2018) J. Infect. Dis. 217, 1809u20131820 was inadvertently reused in Fig. 3C of the article. The images from 8-week WT-infected guinea pigs published in Arora, G., et al. (2018) Front. Cell. Infect. Microbiol. 8, 385 and Singh, M., et al. (2016) Sci. Rep. 6, 26900 were inadvertently reused in Fig. 5, C and D, of the article. The error happened as experimental data shown in each of the articles were derived from the same experiment in which the growth patterns of multiple mutant strains were compared with the parental WT strain in vitro and in vivo. The authors apologize to the readers and scientific community for these errors and intend to republish these results with necessary corrections and additional data. The authors reaffirm the experimental data and state that these inadvertent mistakes do not affect the results or conclusions of the work. ,