Cellular activation, phagocytosis, and bactericidal activity against group B streptococcus involve parallel myeloid differentiation factor 88-dependent and independent signaling pathways.
Group B streptococci (GBS) vigorously activate inflammatory responses. We reported previously that a secreted GBS "factor" activates phagocytes via Toll-like receptor (TLR)2 and TLR6, but that GBS cell walls activate cells independently of these receptors. We hypothesized that the phagocytic immune functions in response to GBS, such as inflammation, uptake, and elimination of bacteria, occur through a coordinated engagement of TLRs, along with the coreceptors CD14 and CD11b/CD18. Using various knockout mice we show that GBS-induced activation of p38 and NF-kappaB depends upon the expression of the cytoplasmic TLR adapter protein, myeloid differentiation factor 88 (MyD88), but not TLR2 and/or TLR4. Macrophages with deletions of CD14 and complement receptor 3 had a normal cytokine response to whole bacteria, although the response to GBS factor was abrogated in CD14-null cells. The intracellular formation of bactericidal oxygen species proved to be MyD88 dependent; however, uptake of GBS, a prerequisite for intracellular killing by O(2) radicals, occurred independently of MyD88. While deletion of complement receptor 3 greatly diminished the uptake of opsonized GBS, it did not affect the formation of bactericidal O(2) radicals or inflammatory signaling intermediates. We conclude that the inflammatory, bactericidal, and phagocytic responses to GBS occur via parallel but independent processes.
Henneke
Philipp
P
Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA.
Takeuchi
Osamu
O
Malley
Richard
R
Lien
Egil
E
Ingalls
Robin R
RR
Freeman
Mason W
MW
Mayadas
Tanya
T
Nizet
Victor
V
Akira
Shizuo
S
Kasper
Dennis L
DL
Golenbock
Douglas T
DT
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D000943:Antigens, Differentiation / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D039481:CD11b Antigen / Q000096:biosynthesis / Q000235:genetics; D018821:CD18 Antigens / Q000096:biosynthesis / Q000235:genetics; D016466:CHO Cells; D002478:Cells, Cultured; D006224:Cricetinae; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics; D029721:Drosophila Proteins; D006801:Humans; D007424:Intracellular Fluid / Q000378:metabolism / Q000382:microbiology; D018950:Lipopolysaccharide Receptors / Q000096:biosynthesis / Q000235:genetics; D008262:Macrophage Activation / Q000235:genetics / Q000276:immunology*; D017737:Macrophages, Peritoneal / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology*; D008562:Membrane Glycoproteins / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B / Q000096:biosynthesis / Q000378:metabolism; D010587:Phagocytosis / Q000235:genetics / Q000276:immunology*; D017382:Reactive Oxygen Species / Q000633:toxicity*; D011956:Receptors, Cell Surface / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics; D011971:Receptors, Immunologic / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D013292:Streptococcus agalactiae / Q000254:growth & development / Q000276:immunology*; D013296:Streptococcus pneumoniae / Q000276:immunology; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051217:Toll-Like Receptor 9; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D048868:Adaptor Proteins, Signal Transducing; D000943:Antigens, Differentiation; D039481:CD11b Antigen; D018821:CD18 Antigens; D004268:DNA-Binding Proteins; D029721:Drosophila Proteins; D018950:Lipopolysaccharide Receptors; C507779:MYD88 protein, human; D008562:Membrane Glycoproteins; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B; D017382:Reactive Oxygen Species; D011956:Receptors, Cell Surface; D011971:Receptors, Immunologic; C495342:TLR2 protein, human; C495345:TLR4 protein, human; C495371:TLR9 protein, human; C495370:Tlr9 protein, mouse; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051217:Toll-Like Receptor 9; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha