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Human scFvs That Counteract Bioactivities of Staphylococcus aureus TSST-1.
- Source :
-
Toxins [Toxins (Basel)] 2017 Feb 17; Vol. 9 (2). Date of Electronic Publication: 2017 Feb 17. - Publication Year :
- 2017
-
Abstract
- Some Staphylococcus aureus isolates produced toxic shock syndrome toxin-1 (TSST-1) which is a pyrogenic toxin superantigen (PTSAg). The toxin activates a large fraction of peripheral blood T lymphocytes causing the cells to proliferate and release massive amounts of pro-inflammatory cytokines leading to a life-threatening multisystem disorder: toxic shock syndrome (TSS). PTSAg-mediated-T cell stimulation circumvents the conventional antigenic peptide presentation to T cell receptor (TCR) by the antigen-presenting cell (APC). Instead, intact PTSAg binds directly to MHC-II molecule outside peptide binding cleft and simultaneously cross-links TCR-Vβ region. Currently, there is neither specific TSS treatment nor drug that directly inactivates TSST-1. In this study, human single chain antibodies (HuscFvs) that bound to and neutralized bioactivities of the TSST-1 were generated using phage display technology. Three E. coli clones transfected with TSST-1-bound phages fished-out from the human scFv library using recombinant TSST-1 as bait expressed TSST-1-bound-HuscFvs that inhibited the TSST-1-mediated T cell activation and pro-inflammatory cytokine gene expressions and productions.Computerized simulation, verified by mutations of the residues of HuscFv complementarity determining regions (CDRs),predicted to involve in target binding indicated that the HuscFvs formed interface contact with the toxin residues important for immunopathogenesis. The HuscFvs have high potential for future therapeutic application.
- Subjects :
- Antibodies, Monoclonal, Humanized genetics
Antibodies, Monoclonal, Humanized metabolism
Antibodies, Neutralizing genetics
Antibodies, Neutralizing metabolism
Bacterial Toxins genetics
Bacterial Toxins immunology
Bacterial Toxins metabolism
Cell Surface Display Techniques
Cells, Cultured
Cytokines metabolism
Enterotoxins genetics
Enterotoxins immunology
Enterotoxins metabolism
Escherichia coli genetics
Escherichia coli metabolism
Histocompatibility Antigens Class II metabolism
Host-Pathogen Interactions
Humans
Inflammation Mediators metabolism
Lymphocyte Activation drug effects
Mutation
Protein Binding
Receptors, Antigen, T-Cell, alpha-beta metabolism
Shock, Septic immunology
Shock, Septic metabolism
Shock, Septic microbiology
Single-Chain Antibodies genetics
Single-Chain Antibodies metabolism
Staphylococcal Infections immunology
Staphylococcal Infections metabolism
Staphylococcal Infections microbiology
Staphylococcus aureus genetics
Staphylococcus aureus immunology
Staphylococcus aureus metabolism
Superantigens genetics
Superantigens immunology
Superantigens metabolism
T-Lymphocytes drug effects
T-Lymphocytes immunology
T-Lymphocytes metabolism
T-Lymphocytes microbiology
Antibodies, Monoclonal, Humanized pharmacology
Antibodies, Neutralizing pharmacology
Bacterial Toxins antagonists & inhibitors
Enterotoxins antagonists & inhibitors
Shock, Septic prevention & control
Single-Chain Antibodies pharmacology
Staphylococcal Infections prevention & control
Staphylococcus aureus drug effects
Subjects
Details
- Language :
- English
- ISSN :
- 2072-6651
- Volume :
- 9
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- Toxins
- Publication Type :
- Academic Journal
- Accession number :
- 28218671
- Full Text :
- https://doi.org/10.3390/toxins9020050