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Identification of an Immunodominant region on a Group A Streptococcus T-antigen Reveals Temperature-Dependent Motion in Pili
Structural highlights
FunctionPublication Abstract from PubMedGroup A Streptococcus (GAS) is a globally important pathogen causing a broad range of human diseases. GAS pili are elongated proteins with a backbone comprised repeating T-antigen subunits, which extend from the cell surface and have important roles in adhesion and establishing infection. No GAS vaccines are currently available, but T-antigen-based candidates are in pre-clinical development. This study investigated antibody-T-antigen interactions to gain molecular insight into functional antibody responses to GAS pili. Large, chimeric mouse/human Fab-phage libraries generated from mice vaccinated with the complete T18.1 pilus were screened against recombinant T18.1, a representative two-domain T-antigen. Of the two Fab identified for further characterization, one (designated E3) was cross-reactive and also recognized T3.2 and T13, while the other (H3) was type-specific reacting with only T18.1/T18.2 within a T-antigen panel representative of the major GAS T-types. The epitopes for the two Fab, determined by x-ray crystallography and peptide tiling, overlapped and mapped to the N-terminal region of the T18.1 N-domain. This region is predicted to be buried in the polymerized pilus by the C-domain of the next T-antigen subunit. However, flow cytometry and opsonophagocytic assays showed that these epitopes were accessible in the polymerized pilus at 37 degrees C, though not at lower temperature. This suggests that there is motion within the pilus at physiological temperature, with structural analysis of a covalently linked T18.1 dimer indicating "knee-joint" like bending occurs between T-antigen subunits to expose this immunodominant region. This temperature dependent, mechanistic flexing provides new insight into how antibodies interact with T-antigens during infection. Identification of an immunodominant region on a group A Streptococcus T-antigen reveals temperature-dependent motion in pili.,Raynes JM, Young PG, Lorenz N, Loh JMS, McGregor R, Baker EN, Proft T, Moreland NJ Virulence. 2023 Dec;14(1):2180228. doi: 10.1080/21505594.2023.2180228. PMID:36809931[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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