The Experts below are selected from a list of 6990 Experts worldwide ranked by ideXlab platform
Peter F. Zipfel - One of the best experts on this subject based on the ideXlab platform.
-
tuf of streptococcus pneumoniae is a surface displayed human Complement Regulator binding protein
Molecular Immunology, 2014Co-Authors: Sarbani Mohan, Christine Skerka, Peter F. Zipfel, Teresia Hallstrom, Sven Hammerschmidt, Christian Hertweck, Antje DuddaAbstract:Streptococcus pneumoniae is a Gram-positive bacterium, causing acute sinusitis, otitis media, and severe diseases such as pneumonia, bacteraemia, meningitis and sepsis. Here we identify elongation factor Tu (Tuf) as a new Factor H binding protein of S. pneumoniae. The surface protein PspC which also binds a series of other human immune inhibitors, was the first identified pneumococcal Factor H binding protein of S. pneumoniae. Pneumococcal Tuf, a 55 kDa pneumococcal moonlighting protein which is displayed on the surface of pneumococci, is also located in the cytoplasm and is detected in the culture supernatant. Tuf binds the human Complement inhibitors Factor H, FHL-1, CFHR1 and also the proenzyme plasminogen. Factor H and FHL-1 bound to Tuf, retain their Complement Regulatory activities. Similarly, plasminogen bound to Tuf was accessible for the activator uPA and activated plasmin cleaved the synthetic chromogenic substrate S-2251 as well as the natural substrates fibrinogen and the Complement proteins C3 and C3b. Taken together, Tuf of S. pneumoniae is a new multi-functional bacterial virulence factor that helps the pathogen in Complement escape and likely also in ECM degradation.
-
outer membrane protein olpa contributes to moraxella catarrhalis serum resistance via interaction with factor h and the alternative pathway
The Journal of Infectious Diseases, 2014Co-Authors: Sara Bernhard, Peter F. Zipfel, Christophe Fleury, Iris Koske, Therese Nordstrom, Kristian RiesbeckAbstract:Factor H is an important Complement Regulator of the alternative pathway commonly recruited by pathogens for increased survival in the human host. The respiratory pathogen Moraxella catarrhalis that resides in the mucosa is highly serum resistant and causes otitis media in children and respiratory tract infections in individuals with underlying diseases. In this study, we show that M. catarrhalis binds factor H via the outer membrane protein OlpA. M. catarrhalis serum resistance was dramatically decreased in the absence of either OlpA or factor H, demonstrating that this inhibition of the alternative pathway significantly contributes to the virulence of M. catarrhalis.
-
further structural insights into the binding of Complement factor h by Complement Regulator acquiring surface protein 1 cspa of borrelia burgdorferi
Acta Crystallographica Section F-structural Biology and Crystallization Communications, 2013Co-Authors: Joseph J E Caesar, Reinhard Wallich, Peter Kraiczy, Peter F. Zipfel, Susan M LeaAbstract:Borrelia burgdorferi has evolved many mechanisms of evading the different immune systems across its range of reservoir hosts, including the capture and presentation of host Complement Regulators factor H and factor H-like protein-1 (FHL-1). Acquisition is mediated by a family of Complement Regulator-acquiring surface proteins (CRASPs), of which the atomic structure of CspA (BbCRASP-1) is known and shows the formation of a homodimeric species which is required for binding. Mutagenesis studies have mapped a putative factor H binding site to a cleft between the two subunits. Presented here is a new atomic structure of CspA which shows a degree of flexibility between the subunits which may be critical for factor H scavenging by increasing access to the binding interface and allows the possibility that the assembly can clamp around the bound Complement Regulators.
-
contribution of the infection associated Complement Regulator acquiring surface protein 4 erpc to Complement resistance of borrelia burgdorferi
Clinical & Developmental Immunology, 2012Co-Authors: Claudia Hammerschmidt, Reinhard Wallich, Christine Skerka, Peter F. Zipfel, Teresia Hallstrom, Brian Stevenson, Peter KraiczyAbstract:Borrelia burgdorferi evades Complement-mediated killing by interacting with Complement Regulators through distinct Complement Regulator-acquiring surface proteins (CRASPs). Here, we extend our analyses to the contribution of CRASP-4 in mediating Complement resistance of B. burgdorferi and its interaction with human Complement Regulators. CRASP-4 (also known as ErpC) was immobilized onto magnetic beads and used to capture proteins from human serum. Following Western blotting, factor H (CFH), CFH-related protein 1 (CFHR1), CFHR2, and CFHR5 were identified as ligands of CRASP-4. To analyze the impact of native CRASP-4 on mediating survival of serum-sensitive cells in human serum, a B. garinii strain was generated that ectopically expresses CRASP-4. CRASP-4-producing bacteria bound CFHR1, CFHR2, and CFHR5 but not CFH. In addition, transformed spirochetes deposited significant amounts of lethal Complement components on their surface and were susceptible to human serum, thus indicating that CRASP-4 plays a subordinate role in Complement resistance of B. burgdorferi.
-
Complement Regulator acquiring surface protein 1 of borrelia burgdorferi binds to human bone morphogenic protein 2 several extracellular matrix proteins and plasminogen
The Journal of Infectious Diseases, 2010Co-Authors: Teresia Hallstrom, Reinhard Wallich, Peter Kraiczy, Christine Skerka, Katrin Haupt, Peter Hortschansky, Peter F. ZipfelAbstract:Lyme disease-causing Borrelia burgdorferi spirochetes express up to 5 Complement Regulator-acquiring surface proteins (CRASPs). To better define how CRASP-1 contributes to infection, we aimed to identify novel CRASP-1-binding host proteins. Here, we identified a number of novel human CRASP-1-binding proteins, including bone morphogenic protein 2, collagen I, collagen III, collagen IV, fibronectin, laminin, and plasminogen. The plasminogen-binding regions were located in 2 separate regions of CRASP-1. Our results demonstrated that plasminogen-bound CRASP-1 can be converted to plasmin by the urokinase-type plasminogen activator and that proteolytically active plasmin cleaves the synthetic chromogenic substrate S-2251 and the natural substrate fibrinogen. In conclusion, CRASP-1 is a multifunctional protein of B. 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.
Peter Kraiczy - One of the best experts on this subject based on the ideXlab platform.
-
Table_2_Further Insights Into the Interaction of Human and Animal Complement Regulator Factor H With Viable Lyme Disease Spirochetes.pdf
2019Co-Authors: Jovana Jasmin Mühleip, Yi-pin Lin, Peter KraiczyAbstract:Spirochetes belonging to the Borrelia (B.) burgdorferi sensu lato (s.l.) complex differ in their ability to establish infection and to survive in diverse vertebrate hosts. Association with and adaption to various hosts most likely correlates with the spirochetes' ability to acquire Complement Regulator factor H (FH) to overcome the host's innate immune response. Here we assessed binding of serum FH from human and various animals including bovine, cat, chicken, dog, horse, mouse, rabbit, and rat to viable B. burgdorferi sensu stricto (s.s.), B. afzelii, B. garinii, B. spielmanii, B. valaisiana, and B. lusitaniae. Spirochetes ectopically producing CspA orthologs of B. burgdorferi s.s., B. afzelii, and B. spielmanii, CspZ, ErpC, and ErpP, respectively, were also investigated. Our comparative analysis using viable bacterial cells revealed a striking heterogeneity among Lyme disease spirochetes regarding their FH-binding patterns that almost mirrors the serum susceptibility of the respective borrelial genospecies. Moreover, native CspA from B. burgdorferi s.s., B. afzelii, and B. spielmanii as well as CspZ were identified as key ligands of FH from human, horse, and rat origin while ErpP appears to bind dog and mouse FH and to a lesser extent human FH. By contrast, ErpC did not bind FH from human as well as from animal origin. These findings indicate a strong restriction of distinct borrelial proteins toward binding of polymorphic FH of various vertebrate hosts.
-
Further Insights Into the Interaction of Human and Animal Complement Regulator Factor H With Viable Lyme Disease Spirochetes
Frontiers Media S.A., 2019Co-Authors: Jovana Jasmin Mühleip, Yi-pin Lin, Peter KraiczyAbstract:Spirochetes belonging to the Borrelia (B.) burgdorferi sensu lato (s.l.) complex differ in their ability to establish infection and to survive in diverse vertebrate hosts. Association with and adaption to various hosts most likely correlates with the spirochetes' ability to acquire Complement Regulator factor H (FH) to overcome the host's innate immune response. Here we assessed binding of serum FH from human and various animals including bovine, cat, chicken, dog, horse, mouse, rabbit, and rat to viable B. burgdorferi sensu stricto (s.s.), B. afzelii, B. garinii, B. spielmanii, B. valaisiana, and B. lusitaniae. Spirochetes ectopically producing CspA orthologs of B. burgdorferi s.s., B. afzelii, and B. spielmanii, CspZ, ErpC, and ErpP, respectively, were also investigated. Our comparative analysis using viable bacterial cells revealed a striking heterogeneity among Lyme disease spirochetes regarding their FH-binding patterns that almost mirrors the serum susceptibility of the respective borrelial genospecies. Moreover, native CspA from B. burgdorferi s.s., B. afzelii, and B. spielmanii as well as CspZ were identified as key ligands of FH from human, horse, and rat origin while ErpP appears to bind dog and mouse FH and to a lesser extent human FH. By contrast, ErpC did not bind FH from human as well as from animal origin. These findings indicate a strong restriction of distinct borrelial proteins toward binding of polymorphic FH of various vertebrate hosts
-
Image_1_Further Insights Into the Interaction of Human and Animal Complement Regulator Factor H With Viable Lyme Disease Spirochetes.pdf
2019Co-Authors: Jovana Jasmin Mühleip, Yi-pin Lin, Peter KraiczyAbstract:Spirochetes belonging to the Borrelia (B.) burgdorferi sensu lato (s.l.) complex differ in their ability to establish infection and to survive in diverse vertebrate hosts. Association with and adaption to various hosts most likely correlates with the spirochetes' ability to acquire Complement Regulator factor H (FH) to overcome the host's innate immune response. Here we assessed binding of serum FH from human and various animals including bovine, cat, chicken, dog, horse, mouse, rabbit, and rat to viable B. burgdorferi sensu stricto (s.s.), B. afzelii, B. garinii, B. spielmanii, B. valaisiana, and B. lusitaniae. Spirochetes ectopically producing CspA orthologs of B. burgdorferi s.s., B. afzelii, and B. spielmanii, CspZ, ErpC, and ErpP, respectively, were also investigated. Our comparative analysis using viable bacterial cells revealed a striking heterogeneity among Lyme disease spirochetes regarding their FH-binding patterns that almost mirrors the serum susceptibility of the respective borrelial genospecies. Moreover, native CspA from B. burgdorferi s.s., B. afzelii, and B. spielmanii as well as CspZ were identified as key ligands of FH from human, horse, and rat origin while ErpP appears to bind dog and mouse FH and to a lesser extent human FH. By contrast, ErpC did not bind FH from human as well as from animal origin. These findings indicate a strong restriction of distinct borrelial proteins toward binding of polymorphic FH of various vertebrate hosts.
-
further structural insights into the binding of Complement factor h by Complement Regulator acquiring surface protein 1 cspa of borrelia burgdorferi
Acta Crystallographica Section F-structural Biology and Crystallization Communications, 2013Co-Authors: Joseph J E Caesar, Reinhard Wallich, Peter Kraiczy, Peter F. Zipfel, Susan M LeaAbstract:Borrelia burgdorferi has evolved many mechanisms of evading the different immune systems across its range of reservoir hosts, including the capture and presentation of host Complement Regulators factor H and factor H-like protein-1 (FHL-1). Acquisition is mediated by a family of Complement Regulator-acquiring surface proteins (CRASPs), of which the atomic structure of CspA (BbCRASP-1) is known and shows the formation of a homodimeric species which is required for binding. Mutagenesis studies have mapped a putative factor H binding site to a cleft between the two subunits. Presented here is a new atomic structure of CspA which shows a degree of flexibility between the subunits which may be critical for factor H scavenging by increasing access to the binding interface and allows the possibility that the assembly can clamp around the bound Complement Regulators.
-
erpc a member of the Complement Regulator acquiring family of surface proteins from borrelia burgdorferi possesses an architecture previously unseen in this protein family
Acta Crystallographica Section F-structural Biology and Crystallization Communications, 2013Co-Authors: Joseph J E Caesar, Peter Kraiczy, Steven Johnson, Susan M LeaAbstract:Borrelia burgdorferi is a spirochete responsible for Lyme disease, the most commonly occurring vector-borne disease in Europe and North America. The bacterium utilizes a set of proteins, termed Complement Regulator-acquiring surface proteins (CRASPs), to aid evasion of the human Complement system by recruiting and presenting Complement Regulator factor H on its surface in a manner that mimics host cells. Presented here is the atomic resolution structure of a member of this protein family, ErpC. The structure provides new insights into the mechanism of recruitment of factor H and other factor H-related proteins by acting as a molecular mimic of host glycosaminoglycans. It also describes the architecture of other CRASP proteins belonging to the OspE/F-related paralogous protein family and suggests that they have evolved to bind specific Complement proteins, aiding survival of the bacterium in different hosts.
Reinhard Wallich - One of the best experts on this subject based on the ideXlab platform.
-
further structural insights into the binding of Complement factor h by Complement Regulator acquiring surface protein 1 cspa of borrelia burgdorferi
Acta Crystallographica Section F-structural Biology and Crystallization Communications, 2013Co-Authors: Joseph J E Caesar, Reinhard Wallich, Peter Kraiczy, Peter F. Zipfel, Susan M LeaAbstract:Borrelia burgdorferi has evolved many mechanisms of evading the different immune systems across its range of reservoir hosts, including the capture and presentation of host Complement Regulators factor H and factor H-like protein-1 (FHL-1). Acquisition is mediated by a family of Complement Regulator-acquiring surface proteins (CRASPs), of which the atomic structure of CspA (BbCRASP-1) is known and shows the formation of a homodimeric species which is required for binding. Mutagenesis studies have mapped a putative factor H binding site to a cleft between the two subunits. Presented here is a new atomic structure of CspA which shows a degree of flexibility between the subunits which may be critical for factor H scavenging by increasing access to the binding interface and allows the possibility that the assembly can clamp around the bound Complement Regulators.
-
contribution of the infection associated Complement Regulator acquiring surface protein 4 erpc to Complement resistance of borrelia burgdorferi
Clinical & Developmental Immunology, 2012Co-Authors: Claudia Hammerschmidt, Reinhard Wallich, Christine Skerka, Peter F. Zipfel, Teresia Hallstrom, Brian Stevenson, Peter KraiczyAbstract:Borrelia burgdorferi evades Complement-mediated killing by interacting with Complement Regulators through distinct Complement Regulator-acquiring surface proteins (CRASPs). Here, we extend our analyses to the contribution of CRASP-4 in mediating Complement resistance of B. burgdorferi and its interaction with human Complement Regulators. CRASP-4 (also known as ErpC) was immobilized onto magnetic beads and used to capture proteins from human serum. Following Western blotting, factor H (CFH), CFH-related protein 1 (CFHR1), CFHR2, and CFHR5 were identified as ligands of CRASP-4. To analyze the impact of native CRASP-4 on mediating survival of serum-sensitive cells in human serum, a B. garinii strain was generated that ectopically expresses CRASP-4. CRASP-4-producing bacteria bound CFHR1, CFHR2, and CFHR5 but not CFH. In addition, transformed spirochetes deposited significant amounts of lethal Complement components on their surface and were susceptible to human serum, thus indicating that CRASP-4 plays a subordinate role in Complement resistance of B. burgdorferi.
-
Complement Regulator acquiring surface protein 1 of borrelia burgdorferi binds to human bone morphogenic protein 2 several extracellular matrix proteins and plasminogen
The Journal of Infectious Diseases, 2010Co-Authors: Teresia Hallstrom, Reinhard Wallich, Peter Kraiczy, Christine Skerka, Katrin Haupt, Peter Hortschansky, Peter F. ZipfelAbstract:Lyme disease-causing Borrelia burgdorferi spirochetes express up to 5 Complement Regulator-acquiring surface proteins (CRASPs). To better define how CRASP-1 contributes to infection, we aimed to identify novel CRASP-1-binding host proteins. Here, we identified a number of novel human CRASP-1-binding proteins, including bone morphogenic protein 2, collagen I, collagen III, collagen IV, fibronectin, laminin, and plasminogen. The plasminogen-binding regions were located in 2 separate regions of CRASP-1. Our results demonstrated that plasminogen-bound CRASP-1 can be converted to plasmin by the urokinase-type plasminogen activator and that proteolytically active plasmin cleaves the synthetic chromogenic substrate S-2251 and the natural substrate fibrinogen. In conclusion, CRASP-1 is a multifunctional protein of B. 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.
-
identification and characterization of the factor h and fhl 1 binding Complement Regulator acquiring surface protein 1 of the lyme disease spirochete borrelia spielmanii sp nov
International Journal of Medical Microbiology, 2009Co-Authors: Pia Herzberger, Christine Skerka, Peter F. Zipfel, Volker Brade, Corinna Siegel, Volker Fingerle, Ulrike Schultespechtel, Bettina Wilske, Reinhard WallichAbstract:Borrelia spielmanii, one of the etiological agents of Lyme disease found in Europe, evades host Complement-mediated killing by recruitment of the immune Regulators factor H and FHL-1 from human serum. Serum-resistant and intermediate serum-resistant isolates express up to 3 distinct Complement Regulator-acquiring surface proteins (CRASPs) that bind factor H and/or FHL-1. The present study describes identification and functional characterization of BsCRASP-1 as the dominant factor H and FHL-1 binding protein of B. spielmanii. BsCRASP-1 is a 27.7kDa outer surface lipoprotein, which after processing has a predicted mass of 24.9kDa. BsCRASP-1 is encoded by a single copy gene, cspA, that maps to a linear plasmid of approximately 55kb. Ligand affinity blot techniques revealed that both native and recombinant BsCRASP-1 from different isolates can strongly bind FHL-1, but only weakly factor H. Deletion mutants of recombinant BsCRASP-1 were generated and a high-affinity binding site for factor H and FHL-1 was mapped to its carboxy-terminal 10-amino-acid residue domain. Similarly, the dominant binding site of factor H and FHL-1 was localized to short consensus repeats (SCRs) 5-7. Factor H and FHL-1 maintained cofactor activity for factor I-mediated C3b inactivation when bound to full-length BsCRASP-1 but not to a deletion mutant lacking the carboxy-terminal 10-amino-acid residue domain. In conclusion, BsCRASP-1 binds the host immune Regulators factor H and FHL-1, and is suggested to represent a key molecule of B. spielmanii for Complement resistance. Thus, BsCRASP-1 most likely contributes to persistence of B. spielmanii and to pathogenesis of Lyme disease.
-
deciphering the ligand binding sites in the borrelia burgdorferi Complement Regulator acquiring surface protein 2 required for interactions with the human immune Regulators factor h and factor h like protein 1
Journal of Biological Chemistry, 2008Co-Authors: Corinna Siegel, Markus M. Simon, Reinhard Wallich, Christine Skerka, Peter F. Zipfel, Volker Brade, Brian Stevenson, Katrin Haupt, Johanna SchreiberAbstract:Borrelia burgdorferi, the etiologic agent of Lyme disease, employs sophisticated means to evade killing by its mammalian hosts. One important immune escape mechanism is the inhibition of Complement activation mediated by interactions of the host-derived immune Regulators factor H (CFH) and factor H-like protein 1 (CFHL1) with borrelial Complement Regulator-acquiring surface proteins (BbCRASPs). BbCRASP-2 is a distinctive CFH- and CFHL1-binding protein that is produced by serum-resistant B. burgdorferi strains. Here we show that binding of CFH by BbCRASP-2 is due to electrostatic as well as hydrophobic forces. In addition, 14 individual amino acid residues of BbCRASP-2 were identified as being involved in CFH and CFHL1 binding. Alanine substitutions of most of those residues significantly inhibited binding of CFH and/or CFHL1 by recombinant BbCRASP-2 proteins. To conclusively define the effects of BbCRASP-2 residue substitutions on serum sensitivity in the bacterial context, a serum-sensitive Borrelia garinii strain was transformed with plasmids that directed production of either wild-type or mutated BbCRASP-2 proteins. Critical amino acid residues within BbCRASP-2 were identified, with bacteria producing distinct mutant proteins being unable to bind either CFH or CFHL1, showing high levels of Complement components C3, C6, and C5b-9 deposited on their surfaces and being highly sensitive to killing by normal serum. Collectively, we mapped a structurally sensitive CFH/CFHL1 binding site within borrelial BbCRASP-2 and identified single amino acid residues potentially involved in the interaction with both Complement Regulators.
Kenji M Cunnion - One of the best experts on this subject based on the ideXlab platform.
-
Complement Regulator c4bp binds to staphylococcus aureus surface proteins sdre and bbp inhibiting bacterial opsonization and killing
Results in Immunology, 2013Co-Authors: Pamela S Hair, Caitlin K Foley, Neel K Krishna, Julius O Nyalwidhe, Joan A Geoghegan, Timothy J Foster, Kenji M CunnionAbstract:Staphylococcus aureus is a premier human pathogen and the most common cause of osteoarticular, wound, and implanted device infections. We recently demonstrated S. aureus efficiently binds the classical Complement Regulator C4b-binding protein (C4BP) inhibiting antibody-initiated Complement-mediated opsonization. Here we identify S. aureus surface protein SdrE as a C4BP-binding protein. Recombinant SdrE and recombinant bone sialoprotein-binding protein (Bbp), an allelic variant of SdrE, both efficiently bound to C4BP in heat-inactivated human serum. We previously described SdrE as binding alternative pathway Regulator factor H. Recombinant SdrE and Bbp efficiently bound C4BP and factor H in serum without apparent interference. Gain of function studies utilizing Lactococcus lactis clones expressing SdrE or Bbp increased serum C4BP and factor H binding, compared with empty-vector control (WT) approximately 2-fold. Correspondingly, classical pathway-mediated C3-fragment opsonization and bacterial killing by human neutrophils decreased by half for L. lactis clones expressing SdrE or Bbp compared with WT. In summary, we identify SdrE and allelic variant Bbp as S. aureus surface proteins that bind the Complement Regulator C4BP inhibiting classical pathway-mediated bacterial opsonization and killing.
-
staphylococcus aureus surface protein sdre binds Complement Regulator factor h as an immune evasion tactic
PLOS ONE, 2012Co-Authors: Julia A Sharp, Pamela S Hair, Julius O Nyalwidhe, Joan A Geoghegan, Timothy J Foster, Kenji M Cunnion, Charlene G Echague, Michael D WardAbstract:Similar to other highly successful invasive bacterial pathogens, Staphylococcus aureus recruits the Complement Regulatory protein factor H (fH) to its surface to inhibit the alternative pathway of Complement. Here, we report the identification of the surface-associated protein SdrE as a fH-binding protein using purified fH overlay of S. aureus fractionated cell wall proteins and fH cross-linking to S. aureus followed by mass spectrometry. Studies using recombinant SdrE revealed that rSdrE bound significant fH whether from serum or as a purified form, in both a time- and dose-dependent manner. Furthermore, rSdrE-bound fH exhibited cofactor functionality for factor I (fI)-mediated cleavage of C3b to iC3b which correlated positively with increasing amounts of fH. Expression of SdrE on the surface of the surrogate bacterium Lactococcus lactis enhanced recruitment of fH which resulted in increased iC3b generation. Moreover, surface expression of SdrE led to a reduction in C3-fragment deposition, less C5a generation, and reduced killing by polymorphonuclear cells. Thus, we report the first identification of a S. aureus protein associated with the staphylococcal surface that binds factor H as an immune evasion mechanism.
-
Complement Regulator c4bp binds to staphylococcus aureus and decreases opsonization
Molecular Immunology, 2012Co-Authors: Pamela S Hair, Julius O Nyalwidhe, Kenji M Cunnion, Sara M Wagner, Patricia T Friederich, Richard R DrakeAbstract:Staphylococcus aureus is the major cause of human skin and soft-tissue infections as well as invasive infections like post-operative wound infections, septic arthritis, and osteomyelitis. The Complement system plays an important role in the immunological control of many bacteria, but can be inhibited by a variety of strategies including recruitment of Complement Regulatory proteins like C4b-binding protein (C4BP). These experiments demonstrate that S. aureus opsonization with C4b occurs rapidly in serum and is predominantly initiated by anti-staphylococcal antibodies. Much of the S. aureus-bound C4b is quickly cleaved to the inactive forms iC4b and C4d. Clinical S. aureus strains rapidly bind significant amounts of the Complement Regulator C4BP from serum. S. aureus also binds purified C4BP. S. aureus-bound C4BP functions as a cofactor for factor I-mediated C4b cleavage to iC4b and C4d. In the absence of factor I, C4BP decreases classical pathway-mediated deposition of C3b on the S. aureus surface by inhibiting the classical pathway C3-convertase. In summary, C4BP is recruited to the S. aureus surface where it functions to inhibit C4 Complement effectors, suggesting a previously undescribed immune evasion strategy for this pathogen.
Andrew Roberts - One of the best experts on this subject based on the ideXlab platform.
-
Complement Regulator cd46 temporally regulates cytokine production by conventional and unconventional t cells
Nature Immunology, 2010Co-Authors: John Cardone, Gaelle Le Friec, Pierre Vantourout, Andrew Roberts, Anja Fuchs, Ian Jackson, Tesha SuddasonAbstract:In this study we demonstrate a new form of immunoregulation: engagement on CD4(+) T cells of the Complement Regulator CD46 promoted the effector potential of T helper type 1 cells (T(H)1 cells), but as interleukin 2 (IL-2) accumulated, it switched cells toward a Regulatory phenotype, attenuating IL-2 production via the transcriptional Regulator ICER/CREM and upregulating IL-10 after interaction of the CD46 tail with the serine-threonine kinase SPAK. Activated CD4(+) T cells produced CD46 ligands, and blocking CD46 inhibited IL-10 production. Furthermore, CD4(+) T cells in rheumatoid arthritis failed to switch, consequently producing excessive interferon-gamma (IFN-gamma). Finally, gammadelta T cells, which rarely produce IL-10, expressed an alternative CD46 isoform and were unable to switch. Nonetheless, coengagement of T cell antigen receptor (TCR) gammadelta and CD46 suppressed effector cytokine production, establishing that CD46 uses distinct mechanisms to regulate different T cell subsets during an immune response.
-
Complement Regulator cd46 temporally regulates cytokine production by conventional and unconventional t cells
Nature Immunology, 2010Co-Authors: John Cardone, Gaelle Le Friec, Pierre Vantourout, Andrew Roberts, Anja Fuchs, Ian Jackson, Tesha Suddason, Graham M LordAbstract:CD46 is best known as a Regulator of Complement function. Kemper et al. show that CD46 can switch inflammatory T cells into a Regulatory mode and demonstrate the molecular details of this process.