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Infection and Immunity, September 2008, p. 4183-4189, Vol. 76, No. 9
0019-9567/08/$08.00+0     doi:10.1128/IAI.00195-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Stages of Meningococcal Sepsis Simulated In Vitro, with Emphasis on Complement and Toll-Like Receptor Activation{triangledown}

Bernt Christian Hellerud,1,2* Jørgen Stenvik,3 Terje Espevik,3 John D. Lambris,4 Tom Eirik Mollnes,2 and Petter Brandtzaeg1,5

Department of Pediatrics, Ullevål University Hospital, and University of Oslo, Oslo, Norway,1 Institute of Immunology, Rikshospitalet University Hospital, and University of Oslo, Oslo, Norway,2 Institute of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway,3 Laboratory of Protein Chemistry, Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania,4 Faculty of Medicine, University of Oslo, Oslo, Norway5

Received 12 February 2008/ Returned for modification 20 March 2008/ Accepted 23 June 2008

The clinical presentation of meningococcal disease is closely related to the number of meningococci in the circulation. This study aimed to examine the activation of the innate immune system after being exposed to increasing and clinically relevant concentrations of meningococci. We incubated representative Neisseria meningitidis serogroup B (ST-32) and serogroup C (ST-11) strains and a lipopolysaccharide (LPS)-deficient mutant (the 44/76 lpxA mutant) in human serum and whole blood and measured complement activation and cytokine secretion and the effect of blocking these systems. HEK293 cells transfected with Toll-like receptors (TLRs) were examined for activation of NF-{kappa}B. The threshold for cytokine secretion and activation of NF-{kappa}B was 103 to 104 meningococci/ml. LPS was the sole inflammation-inducing molecule at concentrations up to 105 to 106 meningococci/ml. The activation was dependent on TLR4-MD2-CD14. Complement contributed to the inflammatory response at ≥105 to 106 meningococci/ml, and complement activation increased exponentially at ≥107 bacteria/ml. Non-LPS components initiated TLR2-mediated activation at ≥107 bacteria/ml. As the bacterial concentration exceeded 107/ml, TLR4 and TLR2 were increasingly activated, independent of CD14. In this model mimicking human disease, the inflammatory response to N. meningitidis was closely associated with the bacterial concentration. Therapeutically, CD14 inhibition alone was most efficient at a low bacterial concentration, whereas addition of a complement inhibitor may be beneficial when the bacterial load increases.

* Corresponding author. Mailing address: Institute of Immunology, Rikshospitalet University Hospital, 0027 Oslo, Norway. Phone: 47 95 92 79 22. Fax: 47 23 07 35 10. E-mail: b.c.hellerud{at}medisin.uio.no

{triangledown} Published ahead of print on 30 June 2008.

Editor: R. P. Morrison

Infection and Immunity, September 2008, p. 4183-4189, Vol. 76, No. 9
0019-9567/08/$08.00+0     doi:10.1128/IAI.00195-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

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