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Infection and Immunity, October 2002, p. 5346-5354, Vol. 70, No. 10
0019-9567/02/$04.00+0     DOI: 10.1128/IAI.70.10.5346-5354.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

The Class A Macrophage Scavenger Receptor Is a Major Pattern Recognition Receptor for Neisseria meningitidis Which Is Independent of Lipopolysaccharide and Not Required for Secretory Responses

Leanne Peiser,1 Menno P. J. de Winther,2 Katherine Makepeace,3 Michael Hollinshead,1 Philip Coull,3 Joyce Plested,3 Tatsuhiko Kodama,4 E. Richard Moxon,3 and Siamon Gordon1*

Sir William Dunn School of Pathology, Oxford University, Oxford, OX1 3RE,1 Institute of Molecular Medicine and Department of Paediatrics, John Radcliffe Hospital, Oxford University, Oxford, OX3 9DU, United Kingdom,3 Department of Molecular Genetics, Maastricht University, 229ER, Maastricht, The Netherlands,2 Department of Molecular Biology and Medicine, Research Center for Advanced Science and Technology, University of Tokyo, Tokyo 153, Japan4

Received 28 January 2002/ Returned for modification 10 April 2002/ Accepted 20 June 2002

Macrophages (M{phi}) play a key role in the pathogenesis of invasive meningococcal infections. The roles of two pattern recognition molecules, the M{phi} scavenger receptor (SR-A) and Toll-like receptor 4 (TLR-4), have been investigated using bone marrow culture-derived M{phi} (BMM{phi}). Surprisingly, a comparison of BMM{phi} from wild-type and SR-A knockout (SR-A-/-) mice showed that nonopsonic phagocytosis of meningococci was mediated almost exclusively via SR-A. Previous studies have demonstrated only a partial involvement of the receptor in the uptake of other bacteria, such as Escherichia coli. Interestingly, we also show that lipopolysaccharide (LPS) was not the ligand for the receptor on these organisms. Further study of the downstream events of SR-A-mediated ingestion of Neisseria meningitidis demonstrated that SR-A was not required for cytokine production. To determine the bacterial and host factors required to stimulate M{phi} activation, we examined TLR-4-deficient M{phi} from C3H/HeJ mice and LPS-deficient meningococci. TLR-4-deficient cells elaborated reduced amounts of tumor necrosis factor alpha, interleukin-12 (IL-12), and IL-10, even though ingestion via SR-A was unaffected in these cells. Similarly, although there was no change in SR-A-mediated ingestion of LPS-deficient meningococci, the mutant failed to stimulate a M{phi}-dependent cytokine response. Thus, we show that M{phi} SR-A mediates opsonin-independent uptake of N. meningitidis independently of lipid A and that this activity is uncoupled from the M{phi} secretion of proinflammatory cytokines, which provides a basis for further investigation of the role of this receptor in meningococcal disease in humans.

* Corresponding author. Mailing address: Sir William Dunn School of Pathology, South Parks Rd., Oxford, OX1 3RE, United Kingdom. Phone: 44-1865-275534. Fax: 44-1865-275515. E-mail: christine.holt{at}path.ox.ac.uk.

Editor: S. H. E. Kaufmann

Infection and Immunity, October 2002, p. 5346-5354, Vol. 70, No. 10
0019-9567/02/$04.00+0     DOI: 10.1128/IAI.70.10.5346-5354.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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