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

Weineisen, MariaLund University,Lunds universitet,Medicinska fakulteten,Faculty of Medicine (författare)

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.

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
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

Sjöbring, UlfLund University,Lunds universitet,Avdelningen för mikrobiologi, immunologi och glykobiologi - MIG,Institutionen för laboratoriemedicin,Medicinska fakulteten,Division of Microbiology, Immunology and Glycobiology - MIG,Department of Laboratory Medicine,Faculty of Medicine(Swepub:lu)mmb-usj (författare)
Fällman, MariaUmeå universitet,Institutionen för molekylärbiologi (Medicinska fakulteten)(Swepub:umu)mafa0002 (författare)
Andersson, TommyLund University,Lunds universitet,Experimentell patologi, Malmö,Forskargrupper vid Lunds universitet,Experimental Pathology, Malmö,Lund University Research Groups(Swepub:lu)expp-tan (författare)
Lunds universitetMedicinska fakulteten (creator_code:org_t)

Av författaren/redakt...: Weineisen, Maria; Sjöbring, Ulf; Fällman, Maria; Andersson, Tommy

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