Elastase-producing Pseudomonas aeruginosa degrade plasma proteins and extracellular products of human skin and fibroblasts, and inhibit fibroblast growth

Schmidtchen, Artur; Holst, Elisabet; Tapper, Hans; Björck, Lars

doi:10.1016/s0882-4010(02)00197-3

Cited by 106 publications

(97 citation statements)

References 45 publications

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“…8, A and B). The endogenous regulatory activity, which is mediated by elastase and alkaline protease, was initially described for several clinical P. aeruginosa isolates (8,9,45). The endogenous C3b cleavage activity varied within the analyzed strains.…”

Section: Discussionmentioning

confidence: 99%

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Immune Evasion of the Human Pathogen Pseudomonas aeruginosa: Elongation Factor Tuf Is a Factor H and Plasminogen Binding Protein

Kunert

Losse

Gruszin

et al. 2007

The Journal of Immunology

205

189

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Pseudomonas aeruginosa is an opportunistic human pathogen that can cause a wide range of clinical symptoms and infections that are frequent in immunocompromised patients. In this study, we show that P. aeruginosa evades human complement attack by binding the human plasma regulators Factor H and Factor H-related protein-1 (FHR-1) to its surface. Factor H binds to intact bacteria via two sites that are located within short consensus repeat (SCR) domains 6–7 and 19–20, and FHR-1 binds within SCR domain 3–5. A P. aeruginosa Factor H binding protein was isolated using a Factor H affinity matrix, and was identified by mass spectrometry as the elongation factor Tuf. Factor H uses the same domains for binding to recombinant Tuf and to intact bacteria. Factor H bound to recombinant Tuf displayed cofactor activity for degradation of C3b. Similarly Factor H bound to intact P. aeruginosa showed complement regulatory activity and mediated C3b degradation. This acquired complement control was rather effective and acted in concert with endogenous proteases. Immunolocalization identified Tuf as a surface protein of P. aeruginosa. Tuf also bound plasminogen, and Tuf-bound plasminogen was converted by urokinase plasminogen activator to active plasmin. Thus, at the bacterial surface Tuf acts as a virulence factor and binds the human complement regulator Factor H and plasminogen. Acquisition of host effector proteins to the surface of the pathogen allows complement control and may facilitate tissue invasion.

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Section: Discussionmentioning

confidence: 99%

“…P. aeruginosa exploit multiple strategies for immune evasion (4). The pathogen secretes catalytic enzymes like alkaline protease and elastase, which degrade the complement activation product C3b deposited at the bacterial surface (8,9). In addition, P. aeruginosa expresses LPS variants that interfere with C3b deposition at the surface (5,10).…”

mentioning

confidence: 99%

Immune Evasion of the Human Pathogen Pseudomonas aeruginosa: Elongation Factor Tuf Is a Factor H and Plasminogen Binding Protein

Kunert

Losse

Gruszin

et al. 2007

The Journal of Immunology

205

189

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show abstract

“…Furthermore, opsonization by C3 fragments can be inhibited. For instance, Pseudomonas aeruginosa secretes active proteases that cleave C3b and prevent C3b deposition, and S. aureus cleaves surface-bound C3b, iC3b, and IgG through the conversion of plasminogen to the active protease plasmin on its cell surface by staphylokinase [144,147]. Inhibition of MAC assembly and reduction of cytolytic ability can be achieved simply by virtue of having a thick cell wall, as is the case for Gram-positive bacteria [148,149].…”

Section: Complement Evasion/subversion Strategies Of Microorganismsmentioning

confidence: 99%

Complement and its role in innate and adaptive immune responses

2009

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The complement system plays a crucial role in the innate defense against common pathogens. Activation of complement leads to robust and efficient proteolytic cascades, which terminate in opsonization and lysis of the pathogen as well as in the generation of the classical inflammatory response through the production of potent proinflammatory molecules. More recently, however, the role of complement in the immune response has been expanded due to observations that link complement activation to adaptive immune responses. It is now appreciated that complement is a functional bridge between innate and adaptive immune responses that allows an integrated host defense to pathogenic challenges. As such, a study of its functions allows insight into the molecular underpinnings of host-pathogen interactions as well as the organization and orchestration of the host immune response. This review attempts to summarize the roles that complement plays in both innate and adaptive immune responses and the consequences of these interactions on host defense.

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“…In addition, P. aeruginosa secretes the endogenous proteases elastase and alkaline protease, which degrade and inactivate human complement components, including C1q, C2, and C3b (12,13). Degradation of the opsonin C3b reduces phagocytosis of the pathogen by human neutrophils, and degradation of C3 inhibits fibroblast cell growth (12,14,15). In addition, P. aeruginosa produces an alginate layer that forms a mechanical barrier and that reduces the accessibility and the action of host complement proteins and other plasma defense factors (16).…”

mentioning

confidence: 99%

Dihydrolipoamide Dehydrogenase of Pseudomonas aeruginosa Is a Surface-Exposed Immune Evasion Protein That Binds Three Members of the Factor H Family and Plasminogen

Hallström

Mörgelin

Barthel

et al. 2012

The Journal of Immunology

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The opportunistic human pathogen Pseudomonas aeruginosa causes a wide range of diseases. To cross host innate immune barriers, P. aeruginosa has developed efficient strategies to escape host complement attack. In this study, we identify the 57-kDa dihydrolipoamide dehydrogenase (Lpd) as a surface-exposed protein of P. aeruginosa that binds the four human plasma proteins, Factor H, Factor H-like protein-1 (FHL-1), complement Factor H-related protein 1 (CFHR1), and plasminogen. Factor H contacts Lpd via short consensus repeats 7 and 18–20. Factor H, FHL-1, and plasminogen when bound to Lpd were functionally active. Factor H and FHL-1 displayed complement-regulatory activity, and bound plasminogen, when converted to the active protease plasmin, cleaved the chromogenic substrate S-2251 and the natural substrate fibrinogen. The lpd of P. aeruginosa is a rather conserved gene; a total of 22 synonymous and 3 nonsynonymous mutations was identified in the lpd gene of the 5 laboratory strains and 13 clinical isolates. Lpd is surface exposed and contributes to survival of P. aeruginosa in human serum. Bacterial survival was reduced when Lpd was blocked on the surface prior to challenge with human serum. Similarly, bacterial survival was reduced up to 84% when the bacteria was challenged with complement active serum depleted of Factor H, FHL-1, and CFHR1, demonstrating a protective role of the attached human regulators from complement attack. In summary, Lpd is a novel surface-exposed virulence factor of P. aeruginosa that binds Factor H, FHL-1, CFHR1, and plasminogen, and the Lpd-attached regulators are relevant for innate immune escape and most likely contribute to tissue invasion.

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Elastase-producing Pseudomonas aeruginosa degrade plasma proteins and extracellular products of human skin and fibroblasts, and inhibit fibroblast growth

Cited by 106 publications

References 45 publications

Immune Evasion of the Human Pathogen Pseudomonas aeruginosa: Elongation Factor Tuf Is a Factor H and Plasminogen Binding Protein

Immune Evasion of the Human Pathogen Pseudomonas aeruginosa: Elongation Factor Tuf Is a Factor H and Plasminogen Binding Protein

Complement and its role in innate and adaptive immune responses

Dihydrolipoamide Dehydrogenase of Pseudomonas aeruginosa Is a Surface-Exposed Immune Evasion Protein That Binds Three Members of the Factor H Family and Plasminogen

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