Host Defense II: Acquired Immunity
Constantin A. Bona, Francisco A. Bonilla in Textbook of Immunology, 2019
Many encapsulated organisms (e.g., pneumococci) resist phagocytosis; this resistance is abolished by opsonic antibodies. The staphylococcal surface protein A actually binds IgG antibody. However, protein A binds Fc, leaving the antibody variable regions facing outward. IgG cannot act as an opsonin in this orientation (Fc is unavailable to bind to macrophage receptors). The herpes simplex virus type 1 (HSV-1) genome actually encodes viral IgG Fc receptors; they are present on infected cells and mature virions. These receptors inhibit antibody effector functions by bipolar bridging. An antibody binds to a determinant on the virus surface, then the viral FcR binds Fc before host FcR can interact and activate effector mechanisms (e.g., complement, phagocytes). Both phagocytosis and ADCC are inhibited in this way. Several other pathogens produce their own FcR: HS V-2, varicella-zoster virus, cytomegalovirus, schistosomes, Leishmania, and trypanosomes.
Fibrinolytic Enzymes for Thrombolytic Therapy
Peter Grunwald in Pharmaceutical Biocatalysis, 2019
Staphylokinase is another non-t-PA variant belonging to the third-generation plasminogen activators. It is an extracellular protein produced by Staphylococcus aureus, which forms 1:1 stoichiometric complex with plasmin or plasminogen and activates more plasminogen molecules. SAK is a monomer of 136 amino acids without any disulfide bond and molecular weight is about 15.5 KDa. SAK complexes with plasminogen molecules that are bound to partially degraded fibrin [Sakharov et al., 1996]. α2-antiplasmin inhibits plasminogen-SAK complex in the absence of fibrin, however, in presence of fibrin the lysine binding domain of the complex is occupied, preventing the inhibition by α2-antiplasmin and there is a 4-fold increment in activity with presence of fibrin, thus more specificity towards fibrin (Lijnen et al., 1991).
Fc Receptors
Maurizio Zanetti, J. Donald Capra in The Antibodies, 1999
Bacterial FcR are well known by Immunologists who use them to purify IgG. Six types of IgG receptors can be found on bacteria [106, 107]. Type I receptors are expressed by most strains of Staphylococcus aureus. They are better known as protein A. Protein A is composed of an N-terminal IgG-binding region which contains 5 mutually homologous units which can each bind IgG, and of a C-terminal region that is covalently linked to the cell wall. Protein A can be released as a soluble molecule. Each protein A molecule binds two IgG molecules. Protein A binds human IgG1, IgG2 and IgG4; mouse IgG2a, IgG2b, IgG3 and, with a lower affinity, IgG1; rabbit IgG; and with low affinity, rat IgG2c. Type II receptors are less well characterized. Type III receptors are expressed by streptococci of the groups C and G. They are also known as protein G. They have similar IgG-binding domains as protein A which have however no sequence homology. Protein G binds all four human IgG subclasses; all four mouse IgG subclasses; rabbit IgG; rat IgG2a, IgG2b, IgG2c and, with a lower affinity, IgG1. Types IV, V and VI receptors are expressed by different strains of streptococci and they bind IgG from different species with variable affinities. The possible roles of bacterial FcR during infection remain unknown.
Insights into ultra-low affinity lipase-antibody noncovalent complex binding mechanisms
Published in mAbs, 2022
Elizabeth Sara Hecht, Shrenik Mehta, Aaron T. Wecksler, Ben Aguilar, Nathaniel Swanson, Wilson Phung, Ananya Dubey Kelsoe, W. Henry Benner, Devin Tesar, Robert F. Kelley, Wendy Sandoval, Alavattam Sreedhara
Were lipase antibody complexes to form on-column, during drug purification, the F(ab’)2 domains would be the most solvent-accessible region for lipase binding. Protein A binding of antibodies is known to occur in the Fc portion of the antibody, between the CH2 and CH3 domains.45 The importance of antibody orientation on the beads in a chromatography column is supported in a study examining the impact of antibody load on protein A column, where it was shown that PLBL2 elution increased at a disproportionately greater rate to antibody load.46 The authors proposed that an increasing number of interaction sites on a column could be responsible, and the work reported here specifically suggests that the F(ab’)2 domain orientation could be a critical parameter. Interestingly, the CH1 region highlighted in this study neighbors a region implicated in PLBL2 binding to mAbs, as determined by SPR, and reported in a 2018 patent,47 but this region did not appear as a common site across the mAbs that were tested in this study. Possible differences include buffer composition used in each study or structural differences in the expressed lipases. While our data suggest that there is a common lipase/esterase binding site on the CH1 domain of IgGs, a thorough phylogenetic assessment of lipases/hydrolases is essential to make such a generic claim. Such an analysis is out of scope for this study but could be an interesting exercise for the future.
Effector mechanisms of influenza-specific antibodies: neutralization and beyond
Published in Expert Review of Vaccines, 2018
Federica Sicca, Sam Neppelenbroek, Anke Huckriede
Antibodies directed against influenza virus make use of a variety of effector mechanisms [11,12]. Antibody-mediated neutralization is the most important mechanism and can prevent influenza virus infection of host cells. The ability of antibodies to neutralize influenza virus is correlated with protection and has, therefore, been studied thoroughly [13,14]. The majority of neutralizing antibodies is directed against the highly variable head region of the HA molecule. As such the activity of these antibodies is highly strain-specific. Besides neutralization, antibodies directed against influenza virus can also make use of effector mechanisms, which do not interfere with the initial infection steps but elicit their protective function later in the viral life cycle [15]. More complex immune interactions are needed for the non-neutralizing antibodies to work. In contrast to neutralizing antibodies which target the variable HA molecule, non-neutralizing antibodies can be directed to a variety of influenza virus proteins. While recognition of the target protein is mediated by the variable parts of the antibody molecules, their biological function is determined by the constant parts of the heavy chains, the Fc part. Accordingly, the class and subclass of the antibodies are very important for the type of effector functions they can engage in.
Escalation of antimicrobial resistance among MRSA part 1: focus on global spread
Published in Expert Review of Anti-infective Therapy, 2023
Joseph P. Lynch, George G. Zhanel
Nearly all S. aureus strains express protein A on their surface. Protein A acts to prevent opsonization and phagocytosis [8]. S. aureus may produce numerous virulence factors that influence tissue invasion, cytotoxicity, membrane damage, and intracellular persistence [8–10]. S. aureus isolates exhibit considerable genetic diversity but specific genotypes have been associated with antimicrobial resistance (AMR) and toxin gene profiles [10,11]. More than 30 virulence factors have been reported including: Panton-Valentine leukocidin (PVL), arginine-catabolic mobile element (ACME), toxic-shock syndrome toxin-1 (tst-1), collagen adhesion and other adhesion factors (eno, fnbpA), staphylococcal enterotoxin A (sea), and myriad toxins [11,12]. Additionally, S. aureus produces biofilms that facilitate persistence and spread of the organism [11,12]. The genetic origin of S. aureus can be deduced using: pulse field gel electrophoresis (PFGE); multilocus sequence typing (MLST): Whole Genome Sequencing (WGS), S. aureus protein A (spa); accessory gene regulator (agr) allele; staphylococcus chromosomal cassette (SCC) mec typing (only for MRSA) [13–16].
Related Knowledge Centers
- Antibody
- Opsonin
- Protein
- Staphylococcus Aureus
- Immunoglobulin G
- Phagocytosis
- Two-Component Regulatory System
- Fragment Crystallizable Region
- Fragment Antigen-Binding
- Protein G