Streptococcal M5 protein prevents neutrophil phagocytosis by interfering with CD11b/CD18 receptor-mediated association and signaling.

• Group A streptococci (GAS) are common human pathogens that express major surface-associated virulence factors designated M proteins. In this study, we explored directly the cellular mechanisms behind their supposed ability to prevent phagocytosis. Isolated human neutrophils killed an M-negative GAS mutant (DeltaM5), but not the wild-type parent strain (M5). After 3 h, 3-4 times as many DeltaM5 as M5 bacteria were associated with the neutrophils, and more DeltaM5 than M5 bacteria were ingested. However, there was no statistically significant difference between DeltaM5 and M5 bacteria in regard to the percentage of the neutrophil-associated bacteria that were ingested, indicating that M5 protein prevents an adhesion receptor-dependent association with neutrophils and not the phagocytic machinery per se. Different Abs against CD11b/CD18 (CR3) blocked adhesion and killing of DeltaM5 bacteria, whereas the blocking of two other complement receptors, CD11c/CD18 (CR4) and CD35 (CR1), did not. The CD11b/CD18-mediated killing of DeltaM5 bacteria resulted in protein tyrosine phosphorylations and Cdc42 activation. Furthermore, inhibition of CD11b/CD18 receptor engagement or tyrosine kinase activity blocked the DeltaM5-induced activation of Cdc42 as well as the killing of these bacteria. We conclude that M5 protein interferes with the CD11b/CD18-dependent association between GAS and neutrophils, and thereby blocks subsequent ingestion of the bacteria.

Ämnesord

MEDICIN OCH HÄLSOVETENSKAP  -- Medicinska och farmaceutiska grundvetenskaper -- Immunologi inom det medicinska området (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Basic Medicine -- Immunology in the medical area (hsv//eng)

Nyckelord

Antibodies; Blocking/pharmacology

Antigens; Bacterial/genetics/*physiology

Antigens; CD11b/immunology/*physiology

Antigens; CD18/immunology/*physiology

Bacterial Adhesion/immunology

Bacterial Outer Membrane Proteins/genetics/*physiology

Carrier Proteins/genetics/*physiology

Complement Activation/immunology

Humans

Immunosuppressive Agents/pharmacology

Neutrophils/*immunology/metabolism/*microbiology

Phagocytosis/*immunology

Phosphorylation

Protein-Tyrosine Kinases/physiology

Receptors; Complement/antagonists & inhibitors/physiology

Signal Transduction/*immunology

Streptococcus pyogenes/genetics/*immunology

Tyrosine/metabolism

cdc42 GTP-Binding Protein/metabolism

rac GTP-Binding Proteins/metabolism

Publikations- och innehållstyp

ref (ämneskategori)

art (ämneskategori)