Critical role of the complement system in group B streptococcus-induced tumor necrosis factor alpha release

Infect Immun. 2003 Nov;71(11):6344-53. doi: 10.1128/IAI.71.11.6344-6353.2003.


Group B Streptococcus (GBS) is a major cause of newborn sepsis and meningitis and induces systemic release of tumor necrosis factor alpha (TNF-alpha), believed to play a role in morbidity and mortality. While previous studies have shown that GBS can induce TNF-alpha release from monocytes and macrophages, little is known about the potential modulating effect of plasma or serum on GBS-induced TNF-alpha release, and there are conflicting reports as to the host receptors involved. In a human whole-blood assay system, GBS type III COH-1 potently induced substantial monocyte TNF-alpha release in adult peripheral blood and, due to a higher concentration of monocytes, 10-fold-greater TNF-alpha release in newborn cord blood. Remarkably, GBS-induced TNF-alpha release from human monocytes was enhanced approximately 1000-fold by heat-labile serum components. Experiments employing C2-, C3-, or C7-depleted serum demonstrated that C3 activation via the alternative pathway is crucial for potent GBS-induced TNF-alpha release. Accordingly, whole blood from C3-deficient mice demonstrated significantly reduced GBS-induced TNF-alpha release. Preincubation with human serum enhanced the TNF-alpha-inducing activity of GBS in a C3- and factor B-dependent manner, implying deposition of complement components via the alternative pathway. GBS-induced TNF-alpha release was inhibited by monoclonal antibodies directed against each of the components of CR3 and CR4: the common integrin beta subunit CD18 and the alpha subunits CD11b (of CR3) and CD11c (of CR4). Blood derived from CR3 (CD11b/CD18)-deficient mice demonstrated a markedly diminished TNF-alpha response to GBS. We conclude that the ability of plasma and serum to greatly amplify GBS-induced TNF-alpha release reflects the activity of the alternative complement pathway that deposits fragments on GBS and thereby enhances CR3- and CR4-mediated monocyte activation.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adult
  • Animals
  • Complement C3 / physiology
  • Complement Factor B / physiology
  • Complement System Proteins / physiology*
  • Humans
  • Integrin alphaXbeta2
  • Lipopolysaccharide Receptors / physiology
  • Macrophage-1 Antigen
  • Mice
  • Mice, Inbred C57BL
  • Monocytes / metabolism
  • Serum / physiology
  • Streptococcus agalactiae / immunology*
  • Tumor Necrosis Factor-alpha / biosynthesis*


  • Complement C3
  • Integrin alphaXbeta2
  • Lipopolysaccharide Receptors
  • Macrophage-1 Antigen
  • Tumor Necrosis Factor-alpha
  • Complement System Proteins
  • Complement Factor B