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Infection and Immunity, January 2004, p. 371-380, Vol. 72, No. 1
0019-9567/04/$08.00+0     DOI: 10.1128/IAI.72.1.371-380.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Neisseria meningitidis Lipooligosaccharide Structure-Dependent Activation of the Macrophage CD14/Toll-Like Receptor 4 Pathway

Susu M. Zughaier,1 Yih-Ling Tzeng,1 Shanta M. Zimmer,1 Anup Datta,2 Russell W. Carlson,2 and David S. Stephens1,3,4,5*

Division of Infectious Diseases, Department of Medicine,1 Department of Microbiology and Immunology,4 Emory University School of Medicine, and Department of Veterans Affairs Medical Center,3 Meningitis and Special Pathogens Branch, Centers for Disease Control and Prevention, Atlanta,5 The Complex Carbohydrate Research Center, University of Georgia, Athens, Georgia2

Received 19 May 2003/ Returned for modification 23 July 2003/ Accepted 22 September 2003

Meningococcal lipopoly(oligo)saccharide (LOS) is a major inflammatory mediator of fulminant meningococcal sepsis and meningitis. Highly purified wild-type meningococcal LOS and LOS from genetically defined mutants of Neisseria meningitidis that contained specific mutations in LOS biosynthesis pathways were used to confirm that meningococcal LOS activation of macrophages was CD14/Toll-like receptor 4 (TLR4)-MD-2 dependent and to elucidate the LOS structural requirement for TLR4 activation. Expression of TLR4 but not TLR2 was required, and antibodies to both TLR4 and CD14 blocked meningococcal LOS activation of macrophages. Meningococcal LOS {alpha} or ß chain oligosaccharide structure did not influence CD14/TLR4-MD-2 activation. However, meningococcal lipid A, expressed by meningococci with defects in 3-deoxy-D-manno-octulosonic acid (KDO) biosynthesis or transfer, resulted in an ~10-fold (P < 0.0001) reduction in biologic activity compared to KDO2-containing meningococcal LOS. Removal of KDO2 from LOS by acid hydrolysis also dramatically attenuated cellular responses. Competitive inhibition assays showed similar binding of glycosylated and unglycosylated lipid A to CD14/TLR4-MD-2. A decrease in the number of lipid A phosphate head groups or penta-acylated meningococcal LOS modestly attenuated biologic activity. Meningococcal endotoxin is a potent agonist of the macrophage CD14/TLR4-MD-2 receptor, helping explain the fulminant presentation of meningococcal sepsis and meningitis. KDO2 linked to meningococcal lipid A was structurally required for maximal activation of the human macrophage TLR4 pathway and indicates an important role for KDO-lipid A in endotoxin biologic activity.

* Corresponding author. Mailing address: Department of Medicine, H-153 Emory University Hospital, 1364 Clifton Rd., NE, Atlanta, GA 30322. Phone: (404) 712-1643. Fax: (404) 727-3099. E-mail: dstep01{at}emory.edu.

Editor: B. B. Finlay

Infection and Immunity, January 2004, p. 371-380, Vol. 72, No. 1
0019-9567/04/$08.00+0     DOI: 10.1128/IAI.72.1.371-380.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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