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John D Lambris - One of the best experts on this subject based on the ideXlab platform.
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Complement component c3 the swiss army knife of innate immunity and host defense
Immunological Reviews, 2016Co-Authors: Daniel Ricklin, Edimara S Reis, Dimitrios C Mastellos, Piet Gros, John D LambrisAbstract:As a preformed defense system, Complement faces a delicate challenge in providing an immediate, forceful Response to pathogens even at first encounter, while sparing host cells in the process. For this purpose, it engages a tightly regulated network of plasma proteins, cell surface receptors, and regulators. Complement component C3 plays a particularly versatile role in this process by keeping the cascade alert, acting as a point of convergence of activation pathways, fueling the amplification of the Complement Response, exerting direct effector functions, and helping to coordinate downstream immune Responses. In recent years, it has become evident that nature engages the power of C3 not only to clear pathogens but also for a variety of homeostatic processes ranging from tissue regeneration and synapse pruning to clearing debris and controlling tumor cell progression. At the same time, its central position in immune surveillance makes C3 a target for microbial immune evasion and, if improperly engaged, a trigger point for various clinical conditions. In our review, we look at the versatile roles and evolutionary journey of C3, discuss new insights into the molecular basis for C3 function, provide examples of disease involvement, and summarize the emerging potential of C3 as a therapeutic target.
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therapeutic control of Complement activation at the level of the central component c3
Immunobiology, 2016Co-Authors: Daniel Ricklin, John D LambrisAbstract:The increasing recognition of the Complement system’s association with diseases of the inflammatory spectrum and with biomaterial and transplant-related complications has generated growing interest in the therapeutic modulation of this innate immune cascade. As a central functional hub that largely drives the activation, amplification, and effector generation of the Complement Response, the plasma protein C3 has long been recognized as an attractive target. While pharmacological modulation of C3 activation may offer a powerful opportunity to interfere with or even prevent Complement-driven pathologies, the development of C3 inhibitors has often been accompanied by concerns regarding the safety and feasibility of this approach. Although no C3-targeted inhibitors have thus far been approved for clinical use, several promising concepts and candidates have emerged in recent years. At the same time, experiences from preclinical development and clinical trials are slowly providing a more detailed picture of therapeutic Complement inhibition at the level of C3. This review highlights the current therapeutic strategies to control C3 activation and discusses the possibilities and challenges on the road to bringing C3-targeted therapeutics to the clinic.
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allosteric inhibition of Complement function by a staphylococcal immune evasion protein
Proceedings of the National Academy of Sciences of the United States of America, 2010Co-Authors: Hui Chen, Daniel Ricklin, Brandon L. Garcia, Brian V. Geisbrecht, Apostolia Tzekou, William J. Mcwhorter, Michal Hammel, Georgia Sfyroera, Virgil L Woods, John D LambrisAbstract:The Complement system is a major target of immune evasion by Staphylococcus aureus. Although many evasion proteins have been described, little is known about their molecular mechanisms of action. Here we demonstrate that the extracellular fibrinogen-binding protein (Efb) from S. aureus acts as an allosteric inhibitor by inducing conformational changes in Complement fragment C3b that propagate across several domains and influence functional regions far distant from the Efb binding site. Most notably, the inhibitor impaired the interaction of C3b with Complement factor B and, consequently, formation of the active C3 convertase. As this enzyme complex is critical for both activation and amplification of the Complement Response, its allosteric inhibition likely represents a fundamental contribution to the overall immune evasion strategy of S. aureus.
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Crystallization of human Complement component C3b in the presence of a staphylococcal Complement-inhibitor protein (SCIN).
Acta Crystallographica Section F Structural Biology and Crystallization Communications, 2009Co-Authors: Brandon L. Garcia, John D Lambris, Kasra X. Ramyar, Apostolia Tzekou, William J. Mcwhorter, Brian V. GeisbrechtAbstract:Staphylococcus aureus secretes a number of small proteins that effectively attenuate the human innate immune Response. Among these, the staphylococcal Complement-inhibitor protein (SCIN) disrupts the function of the Complement component 3 (C3) convertase that is initiated through either the classical or the alternative pathway and thereby prevents amplification of the Complement Response on the bacterial surface. Recent studies have shown that SCIN may affect the activities of the C3 convertase by binding in an equimolar fashion to C3b, which is itself an integral although non-enzymatic component of the convertase. In order to better understand the nature of the C3b–SCIN interaction, the hanging-drop vapor-diffusion technique was used to crystallize human C3b in the presence of a recombinant form of SCIN. These crystals diffracted synchrotron X-rays to approximately 6 A Bragg spacing and grew in a primitive tetragonal space group (P41212 or P43212; unit-cell parameters a = b = 128.03, c = 468.59 A). Cell-content analysis of these crystals was consistent with the presence of either two 1:1 complexes or a single 2:2 assembly in the asymmetric unit, both of which correspond to a solvent content of 51.9%. By making use of these crystals, solution of the C3b–SCIN structure should further our understanding of Complement inhibition and immune evasion by this pathogen.
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structure of c3b reveals conformational changes that underlie Complement activity
Nature, 2006Co-Authors: Bert J C Janssen, John D Lambris, Agni Christodoulidou, Andrew A Mccarthy, Piet GrosAbstract:Resistance to infection and clearance of cell debris in mammals depend on the activation of the Complement system, which is an important component of innate and adaptive immunity. Central to the Complement system is the activated form of C3, called C3b, which attaches covalently to target surfaces to amplify Complement Response, label cells for phagocytosis and stimulate the adaptive immune Response. C3b consists of 1,560 amino-acid residues and has 12 domains. It binds various proteins and receptors to effect its functions. However, it is not known how C3 changes its conformation into C3b and thereby exposes its many binding sites. Here we present the crystal structure at 4-A resolution of the activated Complement protein C3b and describe the conformational rearrangements of the 12 domains that take place upon proteolytic activation. In the activated form the thioester is fully exposed for covalent attachment to target surfaces and is more than 85 A away from the buried site in native C3 (ref. 5). Marked domain rearrangements in the alpha-chain present an altered molecular surface, exposing hidden and cryptic sites that are consistent with known putative binding sites of factor B and several Complement regulators. The structural data indicate that the large conformational changes in the proteolytic activation and regulation of C3 take place mainly in the first conversion step, from C3 to C3b. These insights are important for the development of strategies to treat immune disorders that involve Complement-mediated inflammation.
Daniel Ricklin - One of the best experts on this subject based on the ideXlab platform.
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Complement component c3 the swiss army knife of innate immunity and host defense
Immunological Reviews, 2016Co-Authors: Daniel Ricklin, Edimara S Reis, Dimitrios C Mastellos, Piet Gros, John D LambrisAbstract:As a preformed defense system, Complement faces a delicate challenge in providing an immediate, forceful Response to pathogens even at first encounter, while sparing host cells in the process. For this purpose, it engages a tightly regulated network of plasma proteins, cell surface receptors, and regulators. Complement component C3 plays a particularly versatile role in this process by keeping the cascade alert, acting as a point of convergence of activation pathways, fueling the amplification of the Complement Response, exerting direct effector functions, and helping to coordinate downstream immune Responses. In recent years, it has become evident that nature engages the power of C3 not only to clear pathogens but also for a variety of homeostatic processes ranging from tissue regeneration and synapse pruning to clearing debris and controlling tumor cell progression. At the same time, its central position in immune surveillance makes C3 a target for microbial immune evasion and, if improperly engaged, a trigger point for various clinical conditions. In our review, we look at the versatile roles and evolutionary journey of C3, discuss new insights into the molecular basis for C3 function, provide examples of disease involvement, and summarize the emerging potential of C3 as a therapeutic target.
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therapeutic control of Complement activation at the level of the central component c3
Immunobiology, 2016Co-Authors: Daniel Ricklin, John D LambrisAbstract:The increasing recognition of the Complement system’s association with diseases of the inflammatory spectrum and with biomaterial and transplant-related complications has generated growing interest in the therapeutic modulation of this innate immune cascade. As a central functional hub that largely drives the activation, amplification, and effector generation of the Complement Response, the plasma protein C3 has long been recognized as an attractive target. While pharmacological modulation of C3 activation may offer a powerful opportunity to interfere with or even prevent Complement-driven pathologies, the development of C3 inhibitors has often been accompanied by concerns regarding the safety and feasibility of this approach. Although no C3-targeted inhibitors have thus far been approved for clinical use, several promising concepts and candidates have emerged in recent years. At the same time, experiences from preclinical development and clinical trials are slowly providing a more detailed picture of therapeutic Complement inhibition at the level of C3. This review highlights the current therapeutic strategies to control C3 activation and discusses the possibilities and challenges on the road to bringing C3-targeted therapeutics to the clinic.
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allosteric inhibition of Complement function by a staphylococcal immune evasion protein
Proceedings of the National Academy of Sciences of the United States of America, 2010Co-Authors: Hui Chen, Daniel Ricklin, Brandon L. Garcia, Brian V. Geisbrecht, Apostolia Tzekou, William J. Mcwhorter, Michal Hammel, Georgia Sfyroera, Virgil L Woods, John D LambrisAbstract:The Complement system is a major target of immune evasion by Staphylococcus aureus. Although many evasion proteins have been described, little is known about their molecular mechanisms of action. Here we demonstrate that the extracellular fibrinogen-binding protein (Efb) from S. aureus acts as an allosteric inhibitor by inducing conformational changes in Complement fragment C3b that propagate across several domains and influence functional regions far distant from the Efb binding site. Most notably, the inhibitor impaired the interaction of C3b with Complement factor B and, consequently, formation of the active C3 convertase. As this enzyme complex is critical for both activation and amplification of the Complement Response, its allosteric inhibition likely represents a fundamental contribution to the overall immune evasion strategy of S. aureus.
Michael Engelbrecht Nielsen - One of the best experts on this subject based on the ideXlab platform.
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Complement expression in common carp cyprinus carpio l during infection with ichthyophthirius multifiliis
Developmental and Comparative Immunology, 2007Co-Authors: Santiago F Gonzalez, Kurt Buchmann, Michael Engelbrecht NielsenAbstract:Abstract A real-time PCR assay for determination of the Complement Response to infection with the ectoparasite Ichthyophthirius multifiliis in carp is presented. Specific primers were designed for selected genes representing the three pathways of the carp Complement system. The investigated Complement molecules were C1r/s, C3, C4, C5, factor I, factor B/C2-A (Bf/C2-A), mannose-binding lectin (MBL) and MBL-associated serine protease (MASP). The expression of the selected genes was analyzed on RNA extracts from skin, liver, and whole blood from carp at 3, 12, 24, 36, and 48 h post-infection (pi) with I. multifiliis . A pronounced up-regulation of Bf/C2-A, in skin, blood, and liver (250-, 60-, and 4-fold respectively), was observed at later sampling points pi (24–48 h). In addition, an intermediate (from 5 to 13-fold) down-regulation of MASP was observed in skin and liver samples at 36 and 48 h pi with respect to control fish. MBL was expressed only in liver and no variation in the transcription level of this lectin was observed. Complement factor C3 was significantly up-regulated in liver (4-fold up-regulation, 24 h pi). The presented results indicate that infection with the parasite I. multifiliis in carp to a large extent stimulates the expression of Complement molecules. Moreover, the dramatic and early up-regulation of Bf/C2-A in skin indicates a role of this molecule as an acute-phase reactant. Furthermore, our study confirms the role of fish skin as an important extra-hepatic site of expression of Complement molecules as well as an active regulator of Complement expression. Expression of some of the components of the Complement system in blood suggests that leukocytes in carp act as an important extra-hepatic source of Complement molecules.
D Hoole - One of the best experts on this subject based on the ideXlab platform.
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dietary β glucan stimulate Complement and c reactive protein acute phase Responses in common carp cyprinus carpio during an aeromonas salmonicida infection
Fish & Shellfish Immunology, 2013Co-Authors: Nicolas Pionnier, Alberto Falco, Patrick Frost, Joanna J Miest, Ilgiz Irnazarow, Annette K Shrive, D HooleAbstract:The effect of beta-glucans as feed additive on the profile of C-reactive protein (CRP) and Complement acute phase Responses was studied in common carp Cyprinus carpio after exposition to a bacterial infection with Aeromonas salmonicida. Carp were orally administered with beta-glucan (MacroGard (R)) for 14 days with a daily beta-glucan intake of 6 mg per kg body weight. Fish were then intraperitoneally injected with either PBS or 1 x 10(8) bacteria per fish and sampled at time 0, 6, 12, 24, 48, 72, 96 and 120 h post-injection (p.i.) for serum and head kidney, liver and mid-gut tissues. CRP levels and Complement activity were determined in the serum samples whilst the gene expression profiles of CRP and Complement related genes (crp1, crp2, c1r/s, bf/c2, c3 and masp2) were analysed in the tissues by quantitative PCR. Results obtained showed that oral administration of beta-glucan for 14 days significantly increased serum CRP levels up to 2 fold and serum alternative Complement activity (ACP) up to 35 fold. The bacterial infection on its own (i.e. not combined with a beta-glucan feeding) did have significant effects on Complement Response whilst CRP was not detectably induced during the carp acute phase reaction. However, the combination of the infection and the beta-glucan feeding did show significant effects on both CRP and Complement profiles with higher serum CRP levels and serum ACP activity in the beta-glucan fed fish than in the control fed fish. In addition, a distinct organ and time dependent expression profile pattern was detected for all the selected genes: a peak of gene expression first occurred in the head kidney tissue (6 h p.i. or 12 h p.i.), then an up-regulation in the liver several hours later (24 h p.i.) and finally up- or down-regulations in the mid-gut at 24 h p.i. and 72 h p.i. In conclusion, the results of this study suggest that MacroGard (R) stimulated CRP and Complement Responses to A. salmonicida infection in common carp.
Peter F. Zipfel - One of the best experts on this subject based on the ideXlab platform.
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human Complement control and Complement evasion by pathogenic microbes tipping the balance
Molecular Immunology, 2013Co-Authors: Teresia Hallström, Peter F. Zipfel, Kristian RiesbeckAbstract:Complement is a central homeotic system of mammals and represents the first defense line of innate immunity. The human Complement system is aimed to maintain homeostasis by recognizing and removing damaged or modified self material, as well as infectious foreign microbes. However, pathogenic microbes also control and escape the host Complement and immune attack. The increasing resistance of microbial pathogens to either antibiotics or antifungal drugs is a major health problem and is of global interest. Therefore the topic how pathogenic microbes escape human Complement and immune control is of high and of central interest. Identifying and defining the action of proteins involved in this intense immune interaction and understanding how these proteins interact is of relevance to design new control strategies. In this review we summarize the Complement system of the human host and how this cascade drives effector functions. In addition, we summarize how diverse pathogenic microbes control, modulate and block the Complement Response of their host. The characterization of pathogen derived virulence factors and Complement escape proteins reveals patterns of multiplicity, diversity and redundancy among pathogen encoded proteins. Sequence variability of immune and also Complement escape proteins is largely driven by antigenic diversity and adaptive immunity. However common Complement escape principles are, emerging in terms of conserved binding repertoire for host regulators and evasion among the large variety of infectious microbes. These conserved and common escape features are relevant and they provide challenging options for new therapeutic approaches.
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crystallization and preliminary crystallographic analysis of bbcrasp 1 a Complement regulator acquiring surface protein of borrelia burgdorferi
Acta Crystallographica Section D-biological Crystallography, 2004Co-Authors: Frank S Cordes, Peter F. Zipfel, Markus M. Simon, Michael Kirschfink, Peter Kraiczy, Christine Skerka, Pietro Roversi, Volker Brade, Edward D Lowe, Reinhard WallichAbstract:Borrelia burgdorferi is the causative agent of Lyme disease. Serum-resistant strains of the pathogen are able to reduce the host's immune Response to infection by recruiting fluid-phase Complement regulators from the serum. B. burgdorferi Complement regulator-acquiring surface protein-1 (BbCRASP-1) binds factor H and factor-H-like protein-1 to the bacterial surface, where they actively down-regulate Complement Response. Crystals of native and selenomethionine-substituted BbCRASP-1 have been obtained and a native data set to 2.7 A as well as selenomethionine MAD data to 3.2 A resolution have been collected. The selenium substructure has been solved and initial phases have been refined to 3.0 A by density-modification methods. Model building and refinement are under way.