Antibodies against a secreted product of Staphylococcus aureus trigger phagocytic killing

The Journal of Experimental Medicine
Lena ThomerDominique Missiakas

Abstract

Host immunity against bacteria typically involves antibodies that recognize the microbial surface and promote phagocytic killing. Methicillin-resistant Staphylococcus aureus (MRSA) is a frequent cause of lethal bloodstream infection; however, vaccines and antibody therapeutics targeting staphylococcal surface molecules have thus far failed to achieve clinical efficacy. S. aureus secretes coagulase (Coa), which activates host prothrombin and generates fibrin fibrils that protect the pathogen against phagocytosis by immune cells. Because of negative selection, the coding sequence for the prothrombin-binding D1-D2 domain is highly variable and does not elicit cross-protective immune responses. The R domain, tandem repeats of a 27-residue peptide that bind fibrinogen, is conserved at the C terminus of all Coa molecules, but its functional significance is not known. We show here that the R domain enables bloodstream infections by directing fibrinogen to the staphylococcal surface, generating a protective fibrin shield that inhibits phagocytosis. The fibrin shield can be marked with R-specific antibodies, which trigger phagocytic killing of staphylococci and protect mice against lethal bloodstream infections caused by a broad spectru...Continue Reading

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Citations

Mar 10, 2016·The Journal of Experimental Medicine·Clarissa PozziRino Rappuoli
Aug 17, 2016·The Journal of Experimental Medicine·Dominique Missiakas, Olaf Schneewind
May 23, 2017·Natural Product Reports·P Klahn, M Brönstrup
Nov 9, 2017·Frontiers in Immunology·Eileen Uribe-Querol, Carlos Rosales
Jul 22, 2016·PLoS Pathogens·Marta ZapotocznaJames P O'Gara
Nov 23, 2018·Proceedings of the National Academy of Sciences of the United States of America·Urvish TrivediSøren J Sørensen
May 2, 2019·Frontiers in Cellular and Infection Microbiology·Sheila ThomasMagnus Höök
Sep 27, 2019·Current Drug Targets·Victoria A Ploplis, Francis J Castellino
Dec 19, 2017·Journal of Thrombosis and Haemostasis : JTH·L LiesenborghsT Vanassche
Oct 22, 2020·Research : a Science Partner Journal·Zifang ShangWei Huang
Feb 13, 2021·Antibiotics·Christian KranjecDzung B Diep
Mar 16, 2019·Microbiology Spectrum·Kayan Tam, Victor J Torres
Jun 3, 2021·Vaccines·Pietro Speziale, Giampiero Pietrocola
Jun 13, 2020·Journal of Proteome Research·Annette DreisbachJan Maarten van Dijl

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Methods Mentioned

BETA
fluorescence microscopy
ELISA
flow cytometry
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Software Mentioned

Prism
GraphPad
ImageJ

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