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Characterisation of receptor binding by the chemotaxis inhibitory protein of Staphylococcus aureus and the effects of the host immune response

Characterisation of receptor binding by the chemotaxis inhibitory protein of Staphylococcus aureus and the effects of the host immune response
Characterisation of receptor binding by the chemotaxis inhibitory protein of Staphylococcus aureus and the effects of the host immune response

The chemotaxis inhibitory protein of Staphylococcus aureus (CHIPS) is reported to bind to the receptors for C5a and formylated peptides and has been proposed as a promising lead for the development of new anti-inflammatory compounds. Here we have examined the receptor specificity and mode of action of recombinant CHIPS(28-149) and also the immune response to CHIPS(28-149) in patients with S. aureus infections and in uninfected controls. Recombinant CHIPS(28-149) bound with high affinity to the human C5a receptor (C5aR), but had low affinity for the second C5a receptor, C5L2, and the formyl peptide receptor, FPR. Although ligand binding to C5aR was potently inhibited, CHIPS(28-149) had much weaker effects on ligand binding to C5L2 and FPR. Similarly, CHIPS(28-149) potently inhibited the ligand-induced activation of C5aR but was less potent at inhibition via FPR. NMR studies showed that CHIPS(28-149) bound directly to the N-terminus of C5aR but not C5L2, and CHIPS(28-149) residues involved in the interaction were identified by chemical shift analysis. All human sera examined contained high titres of IgG and IgA reactivity against CHIPS(28-149), and no correlation was observed between infection status at the time of serum collection and antibody titre. Individual serum samples promoted or inhibited the binding of CHIPS(28-149) to C5aR, or had no effect. IgG depletion of serum samples abrogated the effects on CHIPS binding, demonstrating that these were antibody mediated. Sera from infected individuals were more likely to inhibit CHIPS(28-149) binding than sera from healthy controls. However, high antibody titres correlated well with both inhibition and enhancement of CHIPS(28-149) binding to C5aR; this suggests that the inhibitory effect relates to epitope specificity rather than greater antibody binding. We conclude that CHIPS is likely to be too immunogenic to be used as an anti-inflammatory treatment but that some antibodies against CHIPS may be useful in the treatment of S. aureus infections.

Animals, Antibodies, Bacterial, Bacterial Proteins, Calorimetry, Humans, Immunity, Membrane Proteins, Nuclear Magnetic Resonance, Biomolecular, Peptides, Protein Conformation, Protein Interaction Mapping, Receptor, Anaphylatoxin C5a, Receptors, Complement, Recombinant Proteins, Staphylococcal Infections, Staphylococcus aureus, Journal Article, Research Support, Non-U.S. Gov't
0161-5890
2507-2517
Wright, Andrew J.
e5e2160f-6c36-44c8-9bf9-2054a963f7c4
Higginbottom, Adrian
eac36288-eb6c-4cbd-ad71-eda09a1bb096
Philippe, Didier
15ee0645-e943-4185-8bd4-3a3ab80e572c
Upadhyay, Abhishek
f60e7229-a4ca-41f3-afaa-50cb33e4281f
Bagby, Stefan
41286315-9c26-4681-b9ee-7cd9edc40be3
Read, Robert C.
b5caca7b-0063-438a-b703-7ecbb6fc2b51
Monk, Peter N.
20e829a3-5cdf-47da-8aa8-d4f82e8ab7cd
Partridge, Lynda J.
b86f2d4e-1661-4562-9aa2-ecb87246bd9a
Wright, Andrew J.
e5e2160f-6c36-44c8-9bf9-2054a963f7c4
Higginbottom, Adrian
eac36288-eb6c-4cbd-ad71-eda09a1bb096
Philippe, Didier
15ee0645-e943-4185-8bd4-3a3ab80e572c
Upadhyay, Abhishek
f60e7229-a4ca-41f3-afaa-50cb33e4281f
Bagby, Stefan
41286315-9c26-4681-b9ee-7cd9edc40be3
Read, Robert C.
b5caca7b-0063-438a-b703-7ecbb6fc2b51
Monk, Peter N.
20e829a3-5cdf-47da-8aa8-d4f82e8ab7cd
Partridge, Lynda J.
b86f2d4e-1661-4562-9aa2-ecb87246bd9a

Wright, Andrew J., Higginbottom, Adrian, Philippe, Didier, Upadhyay, Abhishek, Bagby, Stefan, Read, Robert C., Monk, Peter N. and Partridge, Lynda J. (2007) Characterisation of receptor binding by the chemotaxis inhibitory protein of Staphylococcus aureus and the effects of the host immune response. Molecular Immunology, 44 (10), 2507-2517. (doi:10.1016/j.molimm.2006.12.022).

Record type: Article

Abstract

The chemotaxis inhibitory protein of Staphylococcus aureus (CHIPS) is reported to bind to the receptors for C5a and formylated peptides and has been proposed as a promising lead for the development of new anti-inflammatory compounds. Here we have examined the receptor specificity and mode of action of recombinant CHIPS(28-149) and also the immune response to CHIPS(28-149) in patients with S. aureus infections and in uninfected controls. Recombinant CHIPS(28-149) bound with high affinity to the human C5a receptor (C5aR), but had low affinity for the second C5a receptor, C5L2, and the formyl peptide receptor, FPR. Although ligand binding to C5aR was potently inhibited, CHIPS(28-149) had much weaker effects on ligand binding to C5L2 and FPR. Similarly, CHIPS(28-149) potently inhibited the ligand-induced activation of C5aR but was less potent at inhibition via FPR. NMR studies showed that CHIPS(28-149) bound directly to the N-terminus of C5aR but not C5L2, and CHIPS(28-149) residues involved in the interaction were identified by chemical shift analysis. All human sera examined contained high titres of IgG and IgA reactivity against CHIPS(28-149), and no correlation was observed between infection status at the time of serum collection and antibody titre. Individual serum samples promoted or inhibited the binding of CHIPS(28-149) to C5aR, or had no effect. IgG depletion of serum samples abrogated the effects on CHIPS binding, demonstrating that these were antibody mediated. Sera from infected individuals were more likely to inhibit CHIPS(28-149) binding than sera from healthy controls. However, high antibody titres correlated well with both inhibition and enhancement of CHIPS(28-149) binding to C5aR; this suggests that the inhibitory effect relates to epitope specificity rather than greater antibody binding. We conclude that CHIPS is likely to be too immunogenic to be used as an anti-inflammatory treatment but that some antibodies against CHIPS may be useful in the treatment of S. aureus infections.

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More information

Accepted/In Press date: 17 December 2006
e-pub ahead of print date: 26 January 2007
Published date: April 2007
Keywords: Animals, Antibodies, Bacterial, Bacterial Proteins, Calorimetry, Humans, Immunity, Membrane Proteins, Nuclear Magnetic Resonance, Biomolecular, Peptides, Protein Conformation, Protein Interaction Mapping, Receptor, Anaphylatoxin C5a, Receptors, Complement, Recombinant Proteins, Staphylococcal Infections, Staphylococcus aureus, Journal Article, Research Support, Non-U.S. Gov't

Identifiers

Local EPrints ID: 416319
URI: https://eprints.soton.ac.uk/id/eprint/416319
ISSN: 0161-5890
PURE UUID: 9db77e50-838e-40f6-a1cb-2ae491f785dd
ORCID for Robert C. Read: ORCID iD orcid.org/0000-0002-4297-6728

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Date deposited: 12 Dec 2017 17:30
Last modified: 20 Jul 2019 00:42

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Contributors

Author: Andrew J. Wright
Author: Adrian Higginbottom
Author: Didier Philippe
Author: Abhishek Upadhyay
Author: Stefan Bagby
Author: Robert C. Read ORCID iD
Author: Peter N. Monk
Author: Lynda J. Partridge

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