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Infection and Immunity, November 2003, p. 6344-6353, Vol. 71, No. 11
0019-9567/03/$08.00+0     DOI: 10.1128/IAI.71.11.6344-6353.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Critical Role of the Complement System in Group B Streptococcus-Induced Tumor Necrosis Factor Alpha Release

Ofer Levy,1,2,3* Rochelle M. Jean-Jacques,2 Colette Cywes,2,3 Richard B. Sisson,1 Kol A. Zarember,4 Paul J. Godowski,4 Jennifer L. Christianson,2 Hilde-Kari Guttormsen,2,3 Michael C. Carroll,5 Anne Nicholson-Weller,6 and Michael R. Wessels1,2,3

Division of Infectious Diseases, Children's Hospital,1 Channing Laboratory, Brigham and Women's Hospital,2 Department of Pathology,5 Harvard Medical School,3 Division of Infectious Diseases, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02115,6 Department of Molecular Biology, Genentech, Inc., South San Francisco, California 940804

Received 29 April 2003/ Accepted 14 August 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 ~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-{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 ß 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.

* Corresponding author. Mailing address: Channing Laboratory, 181 Longwood Ave., Boston, MA 02115. Phone: (617) 525-0350. Fax: (617) 731-1541. E-mail: olevy{at}rics.bwh.harvard.edu.

Editor: V. J. DiRita

Infection and Immunity, November 2003, p. 6344-6353, Vol. 71, No. 11
0019-9567/03/$08.00+0     DOI: 10.1128/IAI.71.11.6344-6353.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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