Enteropathogenic Escherichia coli mediates antiphagocytosis through the inhibition of PI 3-kinase-dependent pathways.
The extracellular pathogen enteropathogenic Escherichia coli (EPEC) uses a type III secretion system to inhibit its uptake by macrophages. We show that EPEC antiphagocytosis is independent of the translocated intimin receptor Tir and occurs by preventing F-actin polymerization required for bacterial uptake. EPEC-macrophage contact triggered activation of phosphatidylinositol (PI) 3-kinase, which was subsequently inhibited in a type III secretion-dependent manner. Inhibition of PI 3-kinase significantly reduced uptake of a secretion-deficient mutant, without affecting antiphagocytosis by the wild type, suggesting that EPEC blocks a PI 3-kinase-dependent phagocytic pathway. EPEC specifically inhibited Fc gamma receptor- but not CR3-receptor mediated phagocytosis of opsonized zymosan. We showed that EPEC inhibits PI 3-kinase activity rather than its recruitment to the site of bacterial contact. Phagocytosis of a secretion mutant correlated with the association of PI 3-kinase with tyrosine-phosphorylated proteins, which wild-type EPEC prevented. These results show that EPEC blocks its uptake by inhibiting a PI 3-kinase-mediated pathway, and translocates effectors other than Tir to interfere with actin-driven host cell processes. This constitutes a novel mechanism of phagocytosis avoidance by an extracellular pathogen.
Biotechnology Laboratory, University of British Columbia, Vancouver, BC, V6T 1Z3, Canada.
J
J
Celli
M
M
Olivier
B B
BB
Finlay
D000199:Actins / Q000378:metabolism; D000818:Animals; D001422:Bacterial Adhesion; D001426:Bacterial Proteins / Q000378:metabolism; D002451:Cell Compartmentation; D004789:Enzyme Activation; D004926:Escherichia coli / Q000472:pathogenicity*; D029968:Escherichia coli Proteins; D016177:Macrophage-1 Antigen / Q000378:metabolism; D008264:Macrophages / Q000382:microbiology* / Q000648:ultrastructure; D051379:Mice; D009895:Opsonin Proteins; D010587:Phagocytosis; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases; D021381:Protein Transport; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D011956:Receptors, Cell Surface / Q000378:metabolism; D017452:Receptors, IgG / Q000378:metabolism; D015398:Signal Transduction; D015054:Zymosan / Q000276:immunology
D000199:Actins; D001426:Bacterial Proteins; D029968:Escherichia coli Proteins; D016177:Macrophage-1 Antigen; D009895:Opsonin Proteins; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D011956:Receptors, Cell Surface; D017452:Receptors, IgG; D015054:Zymosan; C109287:Tir protein, E coli