Peter F Zipfel

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..albicans. The authors show that the complement activation fragment C5a, which is formed in response to Candida infection, induces the cellular release of the inflammatory cytokines IL-6 and IL-1β...

..One important immune escape mechanism for evading complement activation is the binding of complement regulators Factor H (CFH) or Factor H-like protein1 (FHL-1) to Complement Regulator-Acquiring Surface Proteins (CRASPs)...

..Candida Pra1 represents a promising candidate for immune interference...

..Therefore, insights into the mechanisms of complement regulation are crucial for understanding disease pathology and for enabling the development of diagnostic tools and therapies for complement-associated diseases...

..These scenarios explain how defects of a single regulator lead to local, organ specific damage...

..Remarkably, pathogenic microbes copy this mechanism of immune surveillance: they mimic the composition of host cell's, bind Factor H to their surface and engage acquired host Factor H for immune disguise...

..Here we describe the role of complement in the retina and summarize the current concept how defective or inappropriate local complement control contributes to inflammation and the pathophysiology of AMD...

..This article explains how alternative pathway activation proceeds and how defective control increases activation, which ultimately leads to endothelial cell damage...

..The atypical form, which occurs in adult patients, is associated with defective complement control...

..In TTP thrombi formation occurs subsequently to the release of multimers of von Willebrand factor (vWF), and in HUS endothelial cell damage is considered the reason for complement and platelet activation leading to thrombus formation...

..Here we summarize the current scenarios of this emerging field which identifies multiple virulence factors and complement evasion strategies, but which at the same time reveals common mechanisms for immune and complement defense...

..This can result in diseases, like severe renal diseases hemolytic uremic syndrome (HUS) and dense deposit disease (DDD), in age related macular degeneration a common form of blindness and also in other forms of autoimmune diseases...

..Here we summarize the most relevant topics and timely issues that were presented and discussed at the 4th International Workshop on Thrombotic Microangiopathies held in Weimar in October 2009 (www.hus-ttp.de)...

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..Thus, Pra1 is, to our knowledge, the first potent fungal complement inhibitor that favors C. albicans immune escape by inactivating and controlling host complement attack at the level of C3...

..Thus, the surface-expressed CaGpm1p is a virulence factor that utilizes the host Factor H, FHL-1, and plasminogen for immune evasion and degradation of extracellular matrices...

..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...

..As a released protein, Pra1 enhances complement control in direct vicinity of the yeast and thus generates an additional protective layer which controls host complement attack...

..burgdorferi that binds to several human extracellular matrix proteins and plasminogen. These interactions may contribute to adhesion, bacterial colonization, and organ tropism and may allow dissemination of B. burgdorferi in the host...

..These findings provide new insights into complement regulation on the cell surface and biosurfaces and likely define the role of CFHR1 in human diseases...

..Screening for both factors is obviously relevant for HUS patients as reduction of CFH autoantibody levels represents a therapeutic option...

..These results suggest that aHUS-associated FH autoantibodies mimic the effect of C-terminal FH mutations, as they inhibit the regulatory function of FH at cell surfaces by blocking its C-terminal recognition region...

..In summary, the V-ATPase subunit Vma7p is involved in vacuolar ion transport and this transport is required for hyphal growth and virulence of C. albicans...

..aureus from host innate immune reactions...

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..In addition, CFHR4 facilitated binding of native CRP to the surface of necrotic cells. Altogether these data identify CFHR4 as a novel ligand for native CRP, and suggest a role for CFHR4 in opsonization of necrotic cells...

..The increased protective capacity of the Tyr(402) Factor H variant allows better and more efficient clearance and removal of cellular debris and reduces inflammation and pathology...

..Recently, an autoimmune aHUS form has been described that is associated with complement factor H (CFH) autoantibodies. The aim of this study was to address the pathologic relevance of CFH autoantibodies in aHUS...

..Protein levels were enhanced 6 h to 5 d after infarction. Thus, mCRP bound to damaged cardiomyocytes recruits C1q to activate and also C4bp to control the classic complement pathway...

..In summary, Ade5,7p interacts with the multifunctional virulence regulator PtdIns 3-kinase Vps34p, and ade5,7 and vps34 null mutant strains show similar phenotypes regarding sensitivity to metal ions, hyphal growth and virulence...

..The identification of CFHR1/CFHR3 deficiency in aHUS patients may lead to the design of new diagnostic approaches, such as enhanced testing for these genes...

..Secretion of complement degrading proteases provides a highly efficient complement defense response of this human pathogenic yeast that acts after the immediate acquisition of host complement regulators to the cell surface...

..These effects explain how mutant factor H causes defective complement control and in HUS-particularly under condition of inflammation and complement activation-causes endothelial cell damage...

..Thus, CFH and CFHR1, when bound on the surface of C. albicans, enhance antimicrobial activity of human neutrophils...

..Thus, Sbi is a multifunctional bacterial protein, which binds host complement components Factor H and C3 as well as IgG and beta(2)-glycoprotein I and interferes with innate immune recognition...

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..In addition, the vps34 null mutant of C. albicans shows defective autophagocytosis. The relevance of these functions for virulence of C. albicans is discussed...

..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...

..Thus, the protease Alp1 is responsible for the observed cleavage and degrades a broad range of different substrates. In summary, we identified a novel mechanism in A. fumigatus that contributes to evasion from the host complement attack...

..Isolates of Borrelia burgdorferi, the causative agent of Lyme disease, express up to 5 distinct complement regulator-acquiring surface proteins (CRASP-1, -2, -3, -4, and -5)...

..These data show that A. fumigatus conidia bind to complement regulators, and these bound host regulators may contribute to evasion of a host complement attack...

..albicans, especially hyphal cells, by human neutrophils and enhances neutrophil antimicrobial responses. However, the fungus can counteract some of these defense mechanisms by releasing soluble Pra1...

..Thus, candida Gpd2 is a novel fungal immune evasion protein that binds several human complement regulators and, in addition, binds human cells...

..Using mouse plasma, the native presumptive FHR proteins were also analyzed in binding assays. In summary, we identify two FHR proteins in mice and for the first time characterize a murine FHR as a heparin- and C3b-binding protein...

..Acquisition of host effector proteins to the surface of the pathogen allows complement control and may facilitate tissue invasion...

..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...

..As a consequence, these processes may lead to AMD pathogenesis...

..The buried type B mutations seem to affect ligand interaction of factor H more severely than the surface-exposed mutations...

..We here summarize the current knowledge about the role or association of CFHR1 and CFHR3 in the human diseases HUS and AMD...

..Thus early diagnosis of DEAP-HUS and immunosuppressive treatments are important factors to treat this particular type of HUS...

..In addition, A. fumigatus interferes with the innate immunity, with both the complement system and defense mechanisms of phagocytes, thereby evading at least in part the innate immune system...

..This complement-inhibitory activity of plasmin provides a new explanation why pathogenic microbes utilize plasmin(ogen) for immune evasion and tissue penetration...

..Altogether these data point to a highly relevant, yet so far underestimated role of factor H for complement control at cellular surfaces, and reveal a decisive role of the factor H C-terminus in host cell recognition and protection...

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..To our knowledge, FHR-4A provides the first evidence for alternative splicing among Factor H-related genes...

..Mutations in this region, as recently reported in patients with familial hemolytic uremic syndrome, may lead to indiscriminatory C attack against self cells...

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..These autoantibodies enhance C3 convertase activity, probably leading to nephritis...

..On the other hand, the lipid-kinase-defective strain and the vps34 null mutant differ in their temperature- and osmotic-stress response. This indicates a possible role for activities different from the lipid kinase function of Vps34p...

..Finally, cellular (ADP-ribosyl)ating activity impairs binding of TopBP1 to Myc-interacting zinc finger protein-1 (Miz-1). The results indicate an influence of post-translational modifications of TopBP1 on its function during DNA repair...

..We, therefore, provide conclusive evidence that gene conversion is responsible for functionally significant CFH mutations in aHUS...

..This provides an effective tool to monitor the accumulation of active recombinant TEV protease in crude extracts and intact cells...

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..In summary, in T cells, the two zinc-finger proteins EGR-4 and EGR-3 interact with the specific nuclear mediator NF-kappaB and control transcription of genes encoding inflammatory cytokines...

..is the key molecule of the complement resistance of spirochetes, and (iii). is distinct from the Erp protein family. Thus, BbCRASP-1 most likely contributes to persistence of B. burgdorferi and to pathogenesis of Lyme disease...

..Hic binds to a previously unrecognized microbial interaction site in the middle part of factor H...

..Thus, defective heparin/glycosaminoglycan-binding site on domains 19 to 20 of FH most probably mediates complement-induced endothelial cell damage in aHUS...

..Based on the results in this report it is conceptually attractive to establish a murine model for aHUS...

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..This indicates a special mechanism for a diagnostic immunoassay based on the combined effect of simultaneous positive and negative signals in a single sample...

..Based on the measured factor H half-life of about 6 days, regular plasma infusions in 2-week intervals were given, which prevented further aHUS episodes and stopped the decline of kidney function...

..Importantly, the respective virulence factors could be exploited in the development of protein-based vaccines against these pathogens...

..To our knowledge, this is the first report of a bacterial pathogen exploiting a soluble complement regulatory protein for entry into host cells...

..Before justification of liver transplantation as the ultimate treatment for these patients, an international registry should be developed to optimize and standardize therapeutic alternatives...

..These structure-function data support previous biochemical observations. Our understanding of the binding between AM and factor H may help in the development of new treatments for diseases in which these molecules play active roles...

..This observation is also of interest for other human diseases in which factor H is involved, such as human factor H-associated form of hemolytic uremic syndrome...

..These antigens may include the recently detected CRASPs...

..Thus, mf of the nematode O. volvulus may evade human complement by binding fH and by promoting inactivation of C3b into iC3b...

..This work demonstrates that pathogens interact with complement regulators in ways that are distinct from the mechanisms used by the host and are thus obvious targets for drug design...

..In conclusion, our present observations disclose a novel, pathophysiological, factor-H dependent mechanism leading to injury of erythrocytes during the course of hemolytic uremic syndrome...

..The characterization of BbCRASP-2 now provides a complete picture of the three diverse complement regulator-binding protein families of B. burgdorferi yielding new insights into the pathogenesis of Lyme disease...

..In contrast to incubation with active complement, H. influenzae had a reduced survival in FH-depleted human serum, thus demonstrating that FH mediates a protective role at the bacterial surface...

..In summary, mutated FH enables complement activation on the surface of platelets and their activation, which may contribute to the development of thrombocytopenia in aHUS...

..In conclusion, the R1210C mutation of complement factor H is a prototypical aHUS mutation that is present as a rare polymorphism in geographically separated human populations...

..As the understanding of DDD increases, novel therapies should be integrated into existing protocols for DDD and evaluated using an open-label Bayesian study design...

..This is the first report describing an immune evasion mechanism utilized by B. spielmanii sp. nov., and it demonstrates the capture of human immune regulators to resist complement-mediated killing...

..hermsii and its resistance to innate immunity...

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..Therefore, dissecting the exact functions of the individual CFHR proteins will provide insights into the pathophysiology of such inflammatory and infectious diseases and will define the therapeutic potential of these proteins...

..The database emphasizes the causative role of the alternative pathway of complement in disease and provides a repository of knowledge to assist future diagnosis and novel therapeutic approaches...

..In summary, the Vac1p protein is required for several cellular pathways, in particular those that control virulence and pathogenicity. Consequently, Vac1p is a novel and interesting target for antifungal drugs...

..Identification of patients with MPGN II caused by defective complement control may allow treatment by replacement of the missing factor via plasma infusion, thus possibly preventing or at least delaying disease progress...

..Together, these data indicate that most of the factor H-binding CRASPs are members of the Erp protein family, which represents a polymorphic class of proteins with similar or identical immunological reactivities...

..This FH web database will facilitate the interpretation of new mutations and polymorphisms when these are identified in patients, and it will clarify the functional role of FH...

..These results provide novel clues for the manipulation of retrovirus replication and vector tropism...

..Binding of regulatory EGR and NFAT factors to these sites and the functional interaction and formation of stable heterodimeric complexes indicate an important role of these factors for gene transcription...