Secreted pH-Regulated Antigen 1 of <i>Candida albicans</i> Blocks Activation and Conversion of Complement C3

Luo, Shanshan; Hartmann, Andrea; Dahse, Hans‐Martin; Skerka, Christine; Zipfel, Peter F.

doi:10.4049/jimmunol.1001011

Cited by 46 publications

(42 citation statements)

References 63 publications

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“…In addition to H. influenzae, the Gram-negative pathogenic bacteria B. burgdorferi (31,45), P. aeruginosa (33), and H. pylori (35), the Gram-positive bacteria S. pneumoniae (30) and S. aureus (46), and also human pathogenic fungi, including C. albicans (36,47) and A. fumigatus (48), bind plasminogen. H. influenzae, similar to many microbial pathogens, expresses at least two plasminogen binding proteins, PE and aspartase.…”

Section: Discussionmentioning

confidence: 99%

Haemophilus influenzae Uses the Surface Protein E To Acquire Human Plasminogen and To Evade Innate Immunity

Barthel

Singh

Riesbeck

et al. 2012

The Journal of Immunology

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Pathogenic microbes acquire the human plasma protein plasminogen to their surface. In this article, we characterize binding of this important coagulation regulator to the respiratory pathogen nontypeable Haemophilus influenzae and identify the Haemophilus surface protein E (PE) as a new plasminogen-binding protein. Plasminogen binds dose dependently to intact bacteria and to purified PE. The plasminogen–PE interaction is mediated by lysine residues and is also affected by ionic strength. The H. influenzae PE knockout strain (nontypeable H. influenzae 3655Δpe) bound plasminogen with ∼65% lower intensity as compared with the wild-type, PE-expressing strain. In addition, PE expressed ectopically on the surface of Escherichia coli also bound plasminogen. Plasminogen, either attached to intact H. influenzae or bound to PE, was accessible for urokinase plasminogen activator. The converted active plasmin cleaved the synthetic substrate S-2251, and the natural substrates fibrinogen and C3b. Using synthetic peptides that cover the complete sequence of the PE protein, the major plasminogen-binding region was localized to a linear 28-aa-long N-terminal peptide, which represents aa 41–68. PE binds plasminogen and also vitronectin, and the two human plasma proteins compete for PE binding. Thus, PE is a major plasminogen-binding protein of the Gram-negative bacterium H. influenzae, and when converted to plasmin, PE-bound plasmin aids in immune evasion and contributes to bacterial virulence.

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Section: Discussionmentioning

confidence: 99%

Haemophilus influenzae Uses the Surface Protein E To Acquire Human Plasminogen and To Evade Innate Immunity

Barthel

Singh

Riesbeck

et al. 2012

The Journal of Immunology

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“…Furthermore, C. albicans may also bind the complement regulatory proteins, such as the complement regulator C4b-binding protein, factor H, FHL-1, and the plasminogen-binding surface protein, on the cell surface in order to inhibit the activation of the complement system (68,69,88). A recently identified C. albicans surface protein, Pra1, has been shown to bind factor H and the C4b-binding protein to regulate complement activation (58,60) and subsequently block the activation and conversion of C3 (59). On the other hand, strikingly, Pra1 also serves as the primary ligand recognized by CR3 and facilitates phagocytosis (99).…”

Section: Evasion Of Candida From the Host Defense Mechanismsmentioning

confidence: 99%

Interplay between Candida albicans and the Mammalian Innate Host Defense

et al. 2012

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Candida albicans is both the most common fungal commensal microorganism in healthy individuals and the major fungal pathogen causing high mortality in at-risk populations, especially immunocompromised patients. In this review, we summarize the interplay between the host innate system and C. albicans, ranging from how the host recognizes, responds, and clears C. albicans infection to how C. albicans evades, dampens, and escapes from host innate immunity.

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“…The Pra1-bound human regulators are functionally active, inhibit complement activation at the fungal surface, and degrade extracellular matrix components (25). As a secreted protein, Pra1 complexes C3 in solution, blocks cleavage of C3 by a C3 convertase, and thus inhibits further complement activation and immune effector functions (55). In addition, secreted Pra1 enhances Factor H-mediated complement control in the fluid phase (25).…”

Section: Discussionmentioning

confidence: 99%

The pH-regulated Antigen 1 of Candida albicans Binds the Human Complement Inhibitor C4b-binding Protein and Mediates Fungal Complement Evasion

Luo

Blom

Rupp

et al. 2011

Journal of Biological Chemistry

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Candida albicans binds and utilizes human complement inhibitors, such as C4b-binding protein (C4BP), Factor H, and FHL-1 for immune evasion. Here, we identify Candida pH-regulated antigen 1 (Pra1) as the first fungal C4BP-binding protein.Recombinant Pra1 binds C4BP, as shown by ELISA and isothermal titration calorimetry, and the Pra1-C4BP interaction is ionic in nature. The Pra1 binding domains within C4BP were localized to the complement control protein domain 4 (CCP4), CCP7, and CCP8. C4BP bound to Pra1 maintains complementinhibitory activity. C4BP and Factor H bind simultaneously to Candida Pra1 and do not compete for binding at physiological levels. A Pra1-overexpressing C. albicans strain, which had about 2-fold Pra1 levels at the surface acquired also about 2-fold C4BP to the surface, compared with the wild type strain CAI4. A Pra1 knock-out strain showed ϳ22% reduced C4BP binding. C4BP captured by C. albicans from human serum inhibits C4b and C3b surface deposition and also maintains cofactor activity. In summary, Candida Pra1 represents the first fungal C4BP-binding surface protein. Pra1, via binding to C4BP, mediates human complement control, thereby favoring the immune and complement evasion of C. albicans.Candida albicans is a dimorphic human pathogenic fungus, which causes superficial as well as systemic infections most frequently in patients undergoing immunosuppressive therapy or long term catheterization (1). Despite currently applied antifungal therapies, both mortality and morbidity mediated by C. albicans are still unacceptably high (2-4). Therefore, new prophylactic and therapeutic strategies are needed to prevent fungal spreading and tissue damage. The identification of novel yeast virulence factors that contribute to pathogenicity is necessary for approaching new strategies to fight and interfere with Candida infections. In this study, we aimed to identify surface proteins that are central for C. albicans innate immune escape.The human complement system forms the first defense line of innate immunity. Upon infection, microbes are immediately attacked by this highly efficient human immune system (5, 6). Complement can be activated via three major pathways. The classical pathway (CP) 2 is mainly induced by antibodies bound to target structures or by C-reactive protein, and the lectin pathway (LP) is activated by binding of mannose-binding lectin or ficolins to mannan-containing structures on surfaces (7-9). The alternative pathway is initiated spontaneously and continuously by randomly generated C3b, and activated C3b can bind directly to any surface and initiate an amplification loop of the alternative pathway (10, 11).Progression of the complement cascade is controlled by fluid phase inhibitors, which are distributed in plasma and body fluid, or surface-bound inhibitors. These inhibitors include C4BP, a 570-kDa plasma glycoprotein, which is the major fluid phase CP and LP inhibitor (12), as well as Factor H and FHL-1 (Factor H-like protein 1), which are the major fluid phase alternative path...

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Secreted pH-Regulated Antigen 1 of Candida albicans Blocks Activation and Conversion of Complement C3

Cited by 46 publications

References 63 publications

Haemophilus influenzae Uses the Surface Protein E To Acquire Human Plasminogen and To Evade Innate Immunity

Haemophilus influenzae Uses the Surface Protein E To Acquire Human Plasminogen and To Evade Innate Immunity

Interplay between Candida albicans and the Mammalian Innate Host Defense

The pH-regulated Antigen 1 of Candida albicans Binds the Human Complement Inhibitor C4b-binding Protein and Mediates Fungal Complement Evasion

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