Imperial College London
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ProfessorShiraneeSriskandan

Faculty of Medicine, Department of Infectious Disease

Professor of Infectious Diseases
 
 
 
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Contact

 

s.sriskandan

 
 
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Assistant

 

Ms Teyanna Gaeta +44 (0)20 3313 1943

 
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Location

 

8N21ACWBCommonwealth BuildingHammersmith Campus

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Summary

 

Publications

Citation

BibTex format

@article{Goldblatt:2019:10.4049/jimmunol.1801688,
author = {Goldblatt, J and Hoffland, A and Lawrenson, RA and Muir, L and Dattani, S and Tsuchiya, T and Kanegasaki, S and Sriskandan, S and Pease, J},
doi = {10.4049/jimmunol.1801688},
journal = {Journal of Immunology},
pages = {3246--3255},
title = {A requirement for neutrophil glycosaminoglycans in chemokine:receptor interactions is revealed by the streptococcal protease SpyCEP},
url = {http://dx.doi.org/10.4049/jimmunol.1801688},
volume = {202},
year = {2019}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
AB  - To evade the immune system, the lethal human pathogen Streptococcus pyogenes produces SpyCEP, an enzyme that cleaves the C-terminal α-helix of CXCL8, resulting in markedly impaired recruitment of neutrophils to sites of invasive infection. The basis for chemokine inactivation by SpyCEP is, however, poorly understood, as the core domain of CXCL8 known to interact with CXCL8 receptors is unaffected by enzymatic cleavage. We examined the in vitro migration of human neutrophils and observed that their ability to efficiently navigate a CXCL8 gradient was compromised following CXCL8 cleavage by SpyCEP. SpyCEP-mediated cleavage of CXCL8 also impaired CXCL8-induced migration of transfectants expressing the human chemokine receptors CXCR1 or CXCR2. Despite possessing an intact N terminus and preserved disulfide bonds, SpyCEP-cleaved CXCL8 had impaired binding to both CXCR1 and CXCR2, pointing to a requirement for the C-terminal α-helix. SpyCEP-cleaved CXCL8 had similarly impaired binding to the glycosaminoglycan heparin. Enzymatic removal of neutrophil glycosaminoglycans was observed to ablate neutrophil navigation of a CXCL8 gradient, whereas navigation of an fMLF gradient remained largely intact. We conclude, therefore, that SpyCEP cleavage of CXCL8 results in chemokine inactivation because of a requirement for glycosaminoglycan binding in productive chemokine:receptor interactions. This may inform strategies to inhibit the activity of SpyCEP, but may also influence future approaches to inhibit unwanted chemokine-induced inflammation.
AU  - Goldblatt,J
AU  - Hoffland,A
AU  - Lawrenson,RA
AU  - Muir,L
AU  - Dattani,S
AU  - Tsuchiya,T
AU  - Kanegasaki,S
AU  - Sriskandan,S
AU  - Pease,J
DO  - 10.4049/jimmunol.1801688
EP  - 3255
PY  - 2019///
SN  - 1550-6606
SP  - 3246
TI  - A requirement for neutrophil glycosaminoglycans in chemokine:receptor interactions is revealed by the streptococcal protease SpyCEP
T2  - Journal of Immunology
UR  - http://dx.doi.org/10.4049/jimmunol.1801688
UR  - http://hdl.handle.net/10044/1/70398
VL  - 202
ER  -
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