<i>Mycobacterium tuberculosis</i>
            with Disruption in Genes Encoding the Phosphate Binding Proteins PstS1 and PstS2 Is Deficient in Phosphate Uptake and Demonstrates Reduced In Vivo Virulence

Peirs, Priska; Lefèvre, Philippe; Boarbi, Samira; Wang, Xiaoming; Denis, Olivier; Braibant, Martine; Pethe, Kévin; Locht, Camille; Huygen, Kris

doi:10.1128/iai.73.3.1898-1902.2005

Cited by 98 publications

(103 citation statements)

References 36 publications

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“…M. tuberculosis mutants deficient in PstS1 and PstS2 showed decreased c.f.u. in lungs and spleens of mice, indicating a role in virulence (Peirs et al, 2005). Vaccination of C57BL/6 mice with PstS3 DNA protected against challenge with M. tuberculosis (Romano et al, 2006).…”

Section: Examples Of Mycobacterial Lipoproteinsmentioning

confidence: 99%

Lipoprotein synthesis in mycobacteria

et al. 2007

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Lipoproteins are a functionally diverse class of secreted bacterial proteins characterized by an Nterminal lipid moiety. The lipid moiety serves to anchor these proteins to the cell surface. Lipoproteins are synthesized as pre-prolipoproteins and mature by post-translational modifications. The post-translational modifications are directed by the lipobox motif located within the signal peptide. Enzymes involved in lipoprotein synthesis are essential in Gram-negative bacteria but not in Gram-positve bacteria. Inactivation of genes involved in lipoprotein synthesis attenuates a variety of Gram-positive pathogens, including Mycobacterium tuberculosis. The attenuated phenotype of these mutants indicates an important role of lipoproteins and lipoprotein synthesis in bacterial virulence. M. tuberculosis, the causative agent of tuberculosis, is one of the most devastating pathogens in the world. This article reviews recent findings on the synthesis, localization and function of lipoproteins in mycobacteria. IntroductionLipoproteins are a functionally heterogeneous class of proteins universally present in bacteria; typically between 1 % and 3 % of bacterial genomes encode lipoproteins (Babu et al., 2006; http://www.mrc-lmb.cam.ac.uk/genomes/ dolop/). Lipoproteins represent a subgroup of secreted proteins characterized by the presence of a lipobox. The lipobox motif is located in the C-terminal part of the leader peptide and consists of four amino acids [LVI/ASTVI/GAS/ C] (Babu et al., 2006). This motif functions as a recognition signal for lipid modification, which is made on the conserved and essential cysteine residue. Precursor lipoproteins are mainly translocated in a Sec-dependent manner across the plasma membrane and are modified subsequently. Recent investigations indicate that lipoproteins may also be translocated by the twin-arginine translocation (Tat) system (McDonough et al., 2005). However, this pathway presumably is of minor importance because the number of lipoproteins translocated via the Tat transporter is rather small. Modification of precursor proteins is mediated by the consecutive activity of three enzymes: phosphatidylglycerol-pre-prolipoprotein diacylglyceryl transferase (Lgt), prolipoprotein signal peptidase/signal peptidase II (LspA) and phospholipid-apolipoprotein Nacyltransferase (Lnt) (Fig. 1). While Lgt and LspA are universally present in bacteria, Lnt has been reported to be restricted to Gram-negatives (Wu, 1996). The lipid residue covalently linked to the conserved cysteine moiety is thought to allow for anchoring of proteins in biological membranes by means of hydrophobic interaction. In Grampositive bacteria, cell-associated lipoproteins are found in the plasma membrane. In Gram-negative bacteria the majority of cell-associated lipoproteins are found in the outer membrane -only about 10 % stay anchored in the plasma membrane. Lipoproteins may be divided into five general groups according to their function in adhesion and invasion, cell wall synthesis, nutrient uptake, degradative process...

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Section: Examples Of Mycobacterial Lipoproteinsmentioning

confidence: 99%

Lipoprotein synthesis in mycobacteria

et al. 2007

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Section: Introductionmentioning

confidence: 99%

“…P. mirabilis HI4320 possesses a pst operon identical in gene organization to that observed in Escherichia coli. Previous studies have suggested that the roles of the Pst transport system in pathogenesis include regulation of invasion (Lucas et al, 2000;Mathew et al, 2001;Sinai & Bavoil, 1993), antibiotic resistance (Soualhine et al, 2005), colonization (Buckles et al, 2006;Daigle et al, 1995;Lamarche et al, 2005;Orihuela et al, 2001;Peirs et al, 2005;Runyen-Janecky et al, 2005), and biofilm formation (Monds et al, 2001).Since (i) earlier work has alluded to the importance of this system during biofilm formation (Monds et al, 2001(Monds et al, , 2007 and (ii) the formation of crystalline biofilms is a characteristic of UTIs associated with P. mirabilis, we hypothesized that the Pst system of P. mirabilis HI4320 is involved in biofilm formation during establishment of a UTI. To assess the role of the Pst system, this study focused upon determining previously undetected in vitro phenotypes of the Dpst mutants by comparing biofilm formation between the wild-type HI4320 and DpstA and DpstS mutants via confocal laser scanning microscopy (CLSM) and quantitative analysis of surface coverage, and by comparing in vitro protein expression of these strains grown planktonically and as a biofilm.…”

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confidence: 99%

The high-affinity phosphate transporter Pst in Proteus mirabilis HI4320 and its importance in biofilm formation

et al. 2009

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Proteus mirabilis causes urinary tract infections (UTIs) in individuals requiring long-term indwelling catheterization. The pathogenesis of this uropathogen is mediated by a number of virulence factors and the formation of crystalline biofilms. In addition, micro-organisms have evolved complex systems for the acquisition of nutrients, including the phosphate-specific transport system, which has been shown to be important in biofilm formation and pathogenesis. A functional Pst system is important during UTIs caused by P. mirabilis HI4320, since transposon mutants in the PstS periplasmic binding protein and the PstA permease protein were attenuated in the CBA mouse model of UTI. These mutants displayed a defect in biofilm formation when grown in human urine. This study focuses on a comparison of the proteomes during biofilm and planktonic growth in phosphate-rich medium and human urine, and microscopic investigations of biofilms formed by the pst mutants. Our data suggest that (i) the Dpst mutants, and particularly the DpstS mutant, are defective in biofilm formation, and (ii) the proteomes of these mutants differ significantly from that of the wild-type. Therefore, since the Pst system of P. mirabilis HI4320 negatively regulates biofilm formation, this system is important for the pathogenesis of these organisms during complicated UTIs. INTRODUCTIONProteus mirabilis -a member of the family Enterobacteriaceae -is the most common aetiological agent responsible for complicated urinary tract infections (UTIs) (Mobley, 1996). Subpopulations at higher risk for infection by this pathogen include those with long-term indwelling catheterization as well as those with structural and functional abnormalities within the urinary tract (Mobley, 1996). Clinical syndromes associated with P. mirabilis include cystitis and pyelonephritis, with possible complications from stone formation and bacteraemia (Mobley, 1996). These micro-organisms survive in the urinary tract by virtue of their production of a battery of virulence factors, including urease, flagella, fimbriae, haemolysin and IgA protease (Belas, 1996;Mobley et al., 1994;Musher et al., 1975;Peerbooms et al., 1984; Walker et al., 1999), and formation of crystalline biofilm on indwelling catheters (Stickler et al., 1993).Biofilm formation -one of the most important mechanisms of pathogenicity of this micro-organism in the urinary tract -may be defined as a community of surface-attached bacteria encased in an extracellular matrix consisting of secreted carbohydrates, proteins and DNA. Indeed, biofilms have been associated with the virulence of a number of pathogens (Castelli et al., 2006). Organisms in these communities display phenotypic differences from planktonic cells, including a slower rate of growth and increased resistance to antibiotics (Lewis, 2001;Stoodley et al., 2002). P. mirabilis biofilms in urine are unique in that the extracellular polysaccharide matrix is enmeshed with struvite and carbonate apatite crystals (Jones et al., 2006).Abbreviations: CLSM, confocal ...

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“…So these findings suggest a strong link between the stringent response and capsular ␣-glucan up-regulation in M. tuberculosis. Interestingly, inactivation of the Pst system is associated with immune modulation and reduced virulence of M. tuberculosis in mice (34,35). This effect might be due to high capsular ␣-glucan levels, which have also been associated with immunomodulation, in these strains (11,13,14,33).…”

Section: Discussionmentioning

confidence: 99%

Inorganic Phosphate Limitation Modulates Capsular Polysaccharide Composition in Mycobacteria

Weerd

Boot

Maaskant

et al. 2016

Journal of Biological Chemistry

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Mycobacterium tuberculosis is protected by an unusual and highly impermeable cell envelope that is critically important for the successful colonization of the host. The outermost surface of this cell envelope is formed by capsular polysaccharides that play an important role in modulating the initial interactions once the bacillus enters the body. Although the bioenzymatic steps involved in the production of the capsular polysaccharides are emerging, information regarding the ability of the bacterium to modulate the composition of the capsule is still unknown. Here, we study the mechanisms involved in regulation of mycobacterial capsule biosynthesis using a high throughput screen for gene products involved in capsular ␣-glucan production. Utilizing this approach we identified a group of mutants that all carried mutations in the ATP-binding cassette phosphate transport locus pst. These mutants collectively exhibited a strong overproduction of capsular polysaccharides, including ␣-glucan and arabinomannan, suggestive of a role for inorganic phosphate (P i ) metabolism in modulating capsular polysaccharide production. These findings were corroborated by the observation that growth under low P i conditions as well as chemical activation of the stringent response induces capsule production in a number of mycobacterial species. This induction is, in part, dependent on factor E. Finally, we show that Mycobacterium marinum, a model organism for M. tuberculosis, encounters P i stress during infection, which shows the relevance of our findings in vivo.

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Mycobacterium tuberculosis with Disruption in Genes Encoding the Phosphate Binding Proteins PstS1 and PstS2 Is Deficient in Phosphate Uptake and Demonstrates Reduced In Vivo Virulence

Cited by 98 publications

References 36 publications

Lipoprotein synthesis in mycobacteria

Lipoprotein synthesis in mycobacteria

The high-affinity phosphate transporter Pst in Proteus mirabilis HI4320 and its importance in biofilm formation

Inorganic Phosphate Limitation Modulates Capsular Polysaccharide Composition in Mycobacteria

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