Group B Streptococcus (GBS) is a major cause of newborn sepsis and meningitis and induces systemic release of tumor necrosis factor alpha (TNF-α), believed to play a role in morbidity and mortality. While previous studies have shown that GBS can induce TNF-α release from monocytes and macrophages, little is known about the potential modulating effect of plasma or serum on GBS-induced TNF-α 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-α release in adult peripheral blood and, due to a higher concentration of monocytes, 10-fold-greater TNF-α release in newborn cord blood. Remarkably, GBS-induced TNF-α release from human monocytes was enhanced ∼1,000-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-α release. Accordingly, whole blood from C3-deficient mice demonstrated significantly reduced GBS-induced TNF-α release. Preincubation with human serum enhanced the TNF-α-inducing activity of GBS in a C3- and factor B-dependent manner, implying deposition of complement components via the alternative pathway. GBS-induced TNF-α release was inhibited by monoclonal antibodies directed against each of the components of CR3 and CR4: the common integrin β subunit CD18 and the α subunits CD11b (of CR3) and CD11c (of CR4). Blood derived from CR3 (CD11b/CD18)-deficient mice demonstrated a markedly diminished TNF-α response to GBS. We conclude that the ability of plasma and serum to greatly amplify GBS-induced TNF-α release reflects the activity of the alternative complement pathway that deposits fragments on GBS and thereby enhances CR3- and CR4-mediated monocyte activation
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