Exopolyphosphatase of Mycobacterium Tuberculosis Might Limit the Growth of Bacteria Which Thrive in Inflamed and Injured Lung

Article Information

Janice Block

Kupat Cholim Leumit, Beit Shemesh, Israel

*Corresponding Author: Janice Block, Kupat Cholim Leumit, Beit Shemesh, Israel 

Received: 19 August 2019; Accepted: 26 August 2019; Published: 29 August 2019

Citation: Janice Block. Exopolyphosphatase of Mycobacterium Tuberculosis Might Limit the Growth of Bacteria Which Thrive in Inflamed and Injured Lung. Archives of Microbiology & Immunology 3 (2019): 102-106.

Share at Facebook


Pulmonary tuberculosis resembles cystic fibrosis and other chronic inflammatory lung diseases in its ability to cause chronic tissue destruction, hypoxia, tissue acidosis, and leakage of blood into the surrounding milieu. Destructive and inflammatory changes of the lung in diseases such as cystic fibrosis support the increased growth of the commensal Prevotella, a bacterial commensal which requires polyphosphate and thrives under inflammatory conditions. Since the nutritional needs of Prevotella are in some ways mirrored by those of the pathogens Pseudomonas aeruginosa and Berkholderia cepacia, it is possible that Prevotella may serve as a marker for these destructive lung pathogens. The biochemical milieu of pulmonary tuberculosis resembles that of other chronic inflammatory lung diseases in its ability to cause inflammation, destruction, tissue acidosis, and bleeding, yet in pulmonary tuberculosis, contrary to expectation, Prevotella species are decreased rather than increased. It is hypothesized that the M. tuberculosis exopolyphosphatase may serve to reduce polyphosphates required by Prevotella species. Since the nutritional needs of P. aeruginosa and B. cepacia resemble those of Prevotella, it is reasonable to hypothesize that addition of exopolyphosphatase might also hamper the growth of these dangerous lung pathogens, as well.


Tuberculosis; Cystic fibrosis; Prevotella; Pseudomonas; Berkholderia; Polyphosphate; Exopolyphosphatase

Tuberculosis articles, Cystic fibrosis articles, Prevotella articles, Pseudomonas articles, Berkholderia articles, Polyphosphate articles, Exopolyphosphatase articles

Article Details

1. Introduction

In some respects, the process of decline in pulmonary tuberculosis resembles that of cystic fibrosis and other chronic inflammatory conditions of the lung.  In all such conditions there may be lung tissue destruction, hypoxia, local tissue acidosis, leakage of blood into the airway, or loss of weight.  Bacterial pathogens involved pulmonary inflammatory processes - such as Pseudomonas aeruginosa and Berkholderia cepacia in cystic fibrosis and various causes of inflammation and bronchiectasis; Mycobacterium tuberculosis in pulmonary tuberculosis - often have similar nutritional requirements for iron and polyphosphate.  Acquisition of polyphosphate depends on the availability of ATP and bacterial polyphosphate kinase, and leakage of blood and heme into the airway supplies the requirement for iron in ample measure.  In the bacterial pathogens above - P. aeruginosa, B. cepacia, and M. tuberculosis - all utilize heme for iron, and all depend on polyphosphate kinase to synthesize polyphosphate [1-8].

Since the composition of pulmonary microbiota depends on local nutritional, inflammatory, and infectious factors, it should come as no surprise that inflammatory disease processes such as cystic fibrosis, bronchiectasis, and toxic lung exposure select for pulmonary commensals which require iron and polyphosphate for survival and growth and which are capable of thriving in an acidic environment.  Prevotella species conform to expectations in both respects: they depend on polyphosphate and iron, and they are capable of growing at lower pH than are many other commensals.  Accordingly, commensal Prevotella species are increased in cystic fibrosis, in toxic insult to the lung, and in other pulmonary infectious/inflammatory conditions [9-16]. 

Given the proclivities of Prevotella, the presence of this commensal may serve as a marker for certain environmental conditions, as well as for bacterial pathogens which are associated with those conditions.  Since Prevotella requires heme iron and polyphosphate for growth and is capable of thriving at low pH, its increased dominance as a commensal in BAL fluid might suggest the increased presence of iron, blood, polyphosphate, and acid within the lung.  Such conditions, as heralded by Prevotella, might also predispose to infection by P. aeruginosa or B. cepacia, lung pathogens whose nutritional needs resemble those of Prevotella, and which may promote acidosis of local tissue.

In the generalization that chronic inflammatory conditions of the lung tend to lead to increased growth of Prevotella, pulmonary tuberculosis is an exception to the rule.  As a pathogen, M. tuberculosis meets all of the presumed criteria for increased growth of Prevotella species:  M. tuberculosis requires both heme iron and polyphosphate, induces leakage of blood into the airway, and is capable of producing an acidic, inflammatory environment within the lung.  In such an environment, one might expect that Prevotella species, and perhaps also Pseudomonas or Berkholderia species, would thrive.  Instead, the opposite is true.  In pulmonary tuberculosis, Prevotella species are decreased rather than increased, and superinfection by organisms such as Pseudomonas or Berkholderia is much rarer in pulmonary tuberculosis than in cystic fibrosis and other causes of bronchiectasis [6,17-20] Why might this be? 

Structural differences aside, one answer is suggested by the unique ability of M. tuberculosis to adjust its metabolism in order to adapt to starvation conditions, such as that of the oxygen and inorganic phosphate-limited environment of the pulmonary granuloma.  This metabolic adaptation, a type of stringent response, is controlled by the enzyme RelMtb.  Inorganic phosphate starvation, hypoxia, and polyphosphate accumulation activate transcription of RelMtb, which upregulates synthesis of the small molecules involved in the stringent response: guanosine 5’-diphosphate 3’diphosphate (ppGpp) and guanosine 5’-triphosphate 3’-diphosphate (pppGpp), together denoted (p)ppGpp.  (p)ppGpp, in turn, serves as a second messenger for the stress response [21].  The result is decreased growth and decreased biofilm formation.

An important aspect of the stringent stress response in M. tuberculosis is that it is triggered both by inorganic phosphate deficit and also by polyphosphate excess.  In M. tuberculosis, polyphosphate is synthesized via the action of polyphosphate kinase and hydrolysed via the action of exopolyphosphatase 2 (ppx2).  When inorganic phosphate is scarce in the local environment, the stringent response regulates growth.  On the other hand, when polyphosphate reaches a critical threshold, once again, the stringent response regulates growth [22,23].

Chuang et. al. (2015) found that, in M. tuberculosis, in a ppx2 knockdown strain, excess accumulation of polyphosphate resulted in growth restriction and reduced biofilm formation [22,23].  The resultant phenotype is one of growth regulation on both ends of the spectrum.  M. tuberculosis differs from pathogens such as P. aeruginosa and B. cepacia in its ability to persist for many years in a latent or semi-latent state within the lung.  It is possible that the regulation of growth by M. tuberculosis during times of plenty might contribute to the ability of M. tuberculosis to evade host immunity, thereby persisting over extended periods of time in a latent or semi-latent state [24]. 

In pulmonary infection by M. tuberculosis, polyphosphate overproduction triggers the stringent response to restrict bacterial growth, which in turn reduces subsequent polyphosphate production by the organism.  Ongoing bacterial exopolyphosphatase activity hydrolyzes polyphosphate, which enables growth, but growth, in turn, requires further production of polyphosphate.  The effect is a tightly regulated system in which less polyphosphate may be available in the surrounding milieu. 

This polyphosphate regulating behavior of M. tuberculosis could have exciting implications for predisposition to superinfection, as well as for growth of associated microbiota such as Prevotella.  In pulmonary tuberculosis, a commensal such as Prevotella would not be expected to lack for heme iron and would not be hampered by the inflammatory milieu.  But thanks to the ongoing activity of mycobacterial exopolyphosphatase and to ongoing growth restriction during times of excess polyphosphate production, what Prevotella might lack is a source of readily available polyphosphate. 

This condition differs from the situation in cystic fibrosis or the situation in traumatic or toxic lung damage.  In these cases, the underlying cause of lung damage is genetic/metabolic or traumatic rather than infectious, and the bacterial regulatory processes and exopolyphosphases of M. tuberculosis do not play a role in limiting environmental polyphosphate.  Perhaps it is for that reason that Prevotella often thrives under such conditions. 

What can be said for Prevotella might also be said for pathogens such as P. aeruginosa and B. cepacia, pathogens which appear to have similar nutritional needs and characteristics to those of Prevotella.  For if M. tuberculosis exopolyphosphatase can control the growth of Prevotella, perhaps an exopolyphosphatase could limit the growth of Pseudomonas and Berkholderia species, as well.  This trait may hold potential for control of pulmonary infection in predisposing conditions such as cystic fibrosis. 


The author acknowledges no source of external funding.

Conflicts of interest

The author declares no conflicts of interest.


  1. Aggarwal S, Ahmad I, Lam A, et. al. Heme scavenging reduces pulmonary endoplasmic reticulum stress, fibrosis, and emphysema. JCI Insight 3 (2018): 21.
  2. Lam A, Vetal N, Matalon S, Aggarwal S. Role of heme in bromine-induced lung injury. Ann N Y Acad Sci 1374 (2017): 105.
  3. Konings AF, Martin LW, Sharples KJ, al. Pseudomonas aeruginosa uses multiple pathways to acquire iron during chronic infection in cystic fibrosis lungs. Infect Immun 81 (2013): 2697.
  4. Rashid MH, Rao NN, Kornberg A. Inorganic polyphosphate is required for motility of bacterial pathogens. J Bacteriol 182 (2000): 1.
  5. Shiba T, Tsutsumi K, Ishige K, Noguchi T. Inorganic polyphosphate and polyphosphate kinase: their novel biological functions and applications. Biochemistry (Mosc.) 65 (2000): 315-323.
  6. Chuang YM, Belchis DA, Karakousis PC. The polyphosphate kinase gene ppk2 is required for Mycobacterium tuberculosis inorganic polyphosphate regulation and virulence. MBio 4 (2013): e00039.
  7. Moriarty TF, Mullan A, McGrath JW, Quinn JP, Elborn JS, Tunney MM. Effect of reduced pH on inorganic polyphosphate accumulation by Burkholderia cepacia complex isolates. Lett Appl Microbiol 42 (2006): 617.
  8. Rashid MH, Kornberg A. Inorganic polyphosphate is needed for swimming, swarming, and twitching motilities of Pseudomonas aeruginosa. Proc Natl Acad Sci USA 97 (2000): 4885.
  9. Takahashi N, Yamada T. Glucose metabolism by Prevotella intermedia and Prevotella nigrescens. Oral Microbiol Immunol 15 (2000): 188.
  10. Leung KP, Folk SP. Effects of porphyrins and inorganic iron on the growth of Prevotella intermedia. FEMS Microbiol Lett 19 (2002): 15.
  11. Ogata T, Kim YH, Masaki, T, et. al. Effects of an increased concentrate diet on rumen pH and the bacterial community in japanese Black beef cattle at different fattening stages. J Vet Med Sci 81 (2019): 968.
  12. Xue F, Nan X, Sun F, et. al. metagenome sequencing to analyze the impacts of thia mine supplementation on ruminal fungi in dairy cows fed high-concentrate diets. AMB Express 8 (2018): 159.
  13. Huffnagle GB, Dickson RP, Lukacs NW. The respiratory tract microbiome and lung inflammation: a two-way street. Mucosal Immunol 10 (2017): 299.
  14. Harris JK, De Groote MA, Sagel SD, al. Molecular identification of bacteria in bronchoalveolar lavage fluid from children with cystic fibrosis. Proc Natl Acad Sci USA 104 (2007): 20529.
  15. Laguna TA, Wagner BD, Williams CB, al. Airway microbiota in bronchoalveolar lavage fluid from clinically well infants with cystic fibrosis. PLoS One 11 (2016): e67649.
  16. Walsh DM, McCullough SD, Yourstone S, al. Alterations in airway microbiota in patients with PaO2/FiO2ratio  ≤ 300 after burn and inhalation injury. PL0S One 12 (2017): e0173848.
  17. Namasivayam S, Sher A, Glickman MS, Wipperman MF. The microbiome and tuberculosis: early evidence for cross talk. mBio 9 (2018): e01420.
  18. Maji A, Misra R, Dhakan DB, et. al. Gut microbiome contributes to impairment of immunity in pulmonary tuberculosis patients by alteration of butyrate and propionate producers. Environ Microbiol 20 (2018): 402.
  19. Luo M, Luo Y, Wu P, et. al. Alternation of gut microbiota in patients with pulmonary tuberculosis. Front Physiol 8 (2017): 822.
  20. Singh R, Singh M, Arora G, Kumar S, Tiwari P, Kidwai S. Polyphosphate deficiency in Mycobacterium tuberculosis is associated with enhanced drug susceptibility and impaired growth in guinea pigs. J Bacteriol 195 (2013): 2839.
  21. Boutte CC, Crosson S. Bacterial lifestyle shapes stringent response activation. Trends Microbiol 21 (2013): 174.
  22. Tiwari P, Gosain TP, Singh M, al. Inorganic polyphosphate accumulation suppresses the dormancy response and virulence in Mycobacterium tuberculosis (2019).
  23. Chuang YM, Bandyopadhyay N, Rifat D, Rubin H, Bader JS, Karakousis PC. Deficiency of the novel exopolyphosphatase Rv1026/PPX2 leads to metabolic downshift and altered cell wall permeability in Mycobacterium tuberculosis 6 (2015): e02428-14.
  24. Tischler AD, Leistikow RL, Kirksey MA, Voskuil MI, McKinney JD. Mycobacterium tuberculosis requires phosphate-responsive gene regulation to resist host immunity. Infection and immunity 81 (2013): 317.

© 2016-2024, Copyrights Fortune Journals. All Rights Reserved