Proteome analysis reveals adaptation ofPseudomonas aeruginosa to the cystic fibrosis lung environment

Sriramulu, Dinesh Diraviam; Nimtz, Manfred; Römling, Ute

doi:10.1002/pmic.200401227

Cited by 55 publications

(57 citation statements)

References 54 publications

(26 reference statements)

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“…We have revealed that the P. aeruginosa PhoPQ system is upregulated during adherence to epithelial cells, as are a number of genes known to be PhoQ or Mg 2ϩ regulated, suggesting that PhoPQ may partially control the adaptation of P. aeruginosa to epithelial surfaces. Several studies have identified phoQ mutations in polymyxin-resistant clinical isolates from both acute and chronic infections (4,43,57,61). Since the PhoPQ system is transcriptionally upregulated upon adherence of the WT to epithelial cells, it is possible this contributes to early adaptations to the lung environment that are later stabilized by a mutation.…”

Section: Discussionmentioning

confidence: 99%

“…Several virulence factors have been characterized for P. aeruginosa; however, their expression and contributions to CF lung disease are still for the most part incompletely defined. It was previously observed in CF that many of the virulence factors proposed to be essential for establishing a lung infection are actually downregulated or lost during the progression to a chronic infection (13,16,51,59,61). Notable bacterial factors that are required for the initial colonization of the lungs but that are downregulated or lost in chronic CF isolates include flagella, pili, proteases, and smooth lipopolysaccharide (LPS).…”

mentioning

confidence: 99%

“…PhoP-PhoQ is one such two-component system that has been identified in many Gramnegative bacteria, including Salmonella, Yersinia, and P. aeruginosa (21,32,50), as playing roles in the detection of Mg 2ϩ levels, cationic peptide resistance, and pathogenesis. P. aeruginosa polymyxin-resistant clinical isolates and early-stage CF isolates have shown dysregulation of this system (4,43,57,61), highlighting its role in resistance and suggesting a possible role in colonization.…”

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confidence: 99%

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The Pseudomonas aeruginosa PhoP-PhoQ Two-Component Regulatory System Is Induced upon Interaction with Epithelial Cells and Controls Cytotoxicity and Inflammation

et al. 2012

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ABSTRACTThe adaptation ofPseudomonas aeruginosato its environment, including the host, is tightly controlled by its network of regulatory systems. The two-component regulatory system PhoPQ has been shown to play a role in the virulence and polymyxin resistance ofP. aeruginosaas well as several other Gram-negative species. Dysregulation of this system has been demonstrated in clinical isolates, yet how it affects virulence ofP. aeruginosais unknown. To investigate this, an assay was used whereby bacteria were cocultured with human bronchial epithelial cells. The interaction of wild-type (WT) bacteria that had adhered to epithelial cells led to a large upregulation of the expression of theoprH-phoP-phoQoperon and its target, thearnlipopolysaccharide (LPS) modification operon, in a PhoQ-dependent manner, compared to cells in the supernatant that had failed to adhere. Relative to the wild type, aphoQmutant cocultured on epithelial cells produced less secreted protease and lipase and, like thephoQmutant,piv,lipH, andlasBmutants demonstrated reduced cytotoxicity toward epithelial cells. Mutation inphoQalso resulted in alterations to lipid A and to increased inflammatory LPS. These data indicate that mutation ofphoQresults in a phenotype that is similar to the less virulent but more inflammatory phenotype of clinical strains isolated from chronic-stage cystic fibrosis lung infections.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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The Pseudomonas aeruginosa PhoP-PhoQ Two-Component Regulatory System Is Induced upon Interaction with Epithelial Cells and Controls Cytotoxicity and Inflammation

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“…E. Smith et al, 2006;Sriramulu et al, 2005). These changes cause bacteria to diversify and to exhibit characteristics differing from isolates found in the environment outside the body.…”

Section: Pathogenesis Of P Aeruginosa In Cfmentioning

confidence: 99%

Outcome and Prevention of Pseudomonas aeruginosa-Staphylococcus aureus Interactions During Pulmonary Infections in Cystic Fibrosis

Mitchell¹,

Malouin²

2012

Cystic Fibrosis - Renewed Hopes Through Research

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“…The secretory proteome (secretome) of clinical strains of P. aeruginosa is known to contain a number of proteases other than LasB, including the elastolytic metalloprotease LasA and the Ser proteinase PrpL (or protease IV) (10,49). In order to establish whether or not LasB was uniquely responsible for the cleavage of uPAR, we compared the proteolytic capacity of the secretome from the LasB-producing strain PAO1 to that of the LasB-deficient strain PDO240, designed on the PAO1 genetic background (37).…”

Section: Soluble Upar Is Cleaved By Lasb Within Both the D1-d2mentioning

confidence: 99%

The Pseudomonas aeruginosa LasB Metalloproteinase Regulates the Human Urokinase-Type Plasminogen Activator Receptor through Domain-Specific Endoproteolysis

Leduc

Beaufort

Bentzmann³

et al. 2007

Infect Immun

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Pseudomonas aeruginosa is an opportunistic pathogen in human lungs, where its secretable LasB metalloproteinase can be a virulence factor. The urokinase-type plasminogen activator receptor (uPAR) participates in pericellular proteolysis and the adherence/migration of epithelial cells and leukocytes recruited during infection and shows functional regulation by various proteinases via limited endoproteolysis occurring within its three domains (D1 to D3). We thus examined the proteolytic activity of LasB on uPAR by using recombinant uPAR as well as uPAR-expressing, human monocytic, and bronchial epithelial cell lines. Protein immunoblotting and flow immunocytometry using a panel of domain-specific anti-uPAR antibodies showed that LasB is able to cleave uPAR both within the sequence linking D1 to D2 and at the carboxy terminus of D3. (D3). Such a dual cleavage of uPAR led to the removal of amino-terminal D1, the generation of a truncated D2D3 species, and the shedding of D2D3 from cells. This proteolytic processing of uPAR was found to (i) drastically reduce the capacity of cells to bind urokinase and (ii) abrogate the interaction between uPAR and the matrix adhesive protein vitronectin. The LasB proteinase is thus endowed with a high potential for the alteration of uPAR expression and functioning on inflammatory cells during infections by P. aeruginosa.Pseudomonas aeruginosa is a gram-negative bacterium that is a major opportunistic pathogen in humans and is capable of infecting various tissues and organs and causing severe, damaging, and often fatal pathologies (42). The lung is a main target for colonization and infection by the bacteria either in the context of a chronic, progressively deteriorating infectious and inflammatory pulmonary disease such as cystic fibrosis (CF) or in a more acute setting such as severe pneumonia in immunocompromised patients (28,45,55). A number of secretable bacterial virulence factors can contribute to the pathogenicity of P. aeruginosa, including proteinases (32,42,45). Among the pseudomonal proteinases is an elastolytic metalloproteinase of the thermolysin/M4 peptidase family that is encoded by the lasB gene, hereafter designated LasB but also known as pseudolysin or P. aeruginosa elastase (36, 38, 41). LasB, a type II secretion system substrate, has received much attention because of its highly regulated expression during tissue colonization and infection, particularly in the lungs (55), and its potential as a virulence factor (32,41,45). Indeed, P. aeruginosa-associated pathogenic processes include both damage to tissues via hydrolysis of extracellular matrix (ECM) components and alterations of endothelial and epithelial barriers (3,15,36,41). It also participates in the proteolytic inactivation of numerous extracellular components of the innate and adaptive immune systems including opsonins, cytokines, chemokines, antibacterial peptides, and proteinase inhibitors (1,9,35,46,51). In addition, more recent studies have shown that the exposure of isolated human leukocytes to LasB...

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Proteome analysis reveals adaptation ofPseudomonas aeruginosa to the cystic fibrosis lung environment

Cited by 55 publications

References 54 publications

The Pseudomonas aeruginosa PhoP-PhoQ Two-Component Regulatory System Is Induced upon Interaction with Epithelial Cells and Controls Cytotoxicity and Inflammation

The Pseudomonas aeruginosa PhoP-PhoQ Two-Component Regulatory System Is Induced upon Interaction with Epithelial Cells and Controls Cytotoxicity and Inflammation

Outcome and Prevention of Pseudomonas aeruginosa-Staphylococcus aureus Interactions During Pulmonary Infections in Cystic Fibrosis

The Pseudomonas aeruginosa LasB Metalloproteinase Regulates the Human Urokinase-Type Plasminogen Activator Receptor through Domain-Specific Endoproteolysis

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