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Infection and Immunity, January 2008, p. 206-213, Vol. 76, No. 1
0019-9567/08/$08.00+0     doi:10.1128/IAI.01140-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Lipoteichoic Acid Is Important in Innate Immune Responses to Gram-Positive Bacteria{triangledown}

Ho Seong Seo,1,2 Suzanne M. Michalek,2 and Moon H. Nahm1,2*

Departments of Pathology,1 Microbiology, University of Alabama at Birmingham, Birmingham, Alabama2

Received 17 August 2007/ Returned for modification 21 September 2007/ Accepted 12 October 2007

To define the role of lipoteichoic acid (LTA) in innate immunity to gram-positive bacteria, we investigated the production of tumor necrosis factor alpha (TNF-{alpha}) by macrophages stimulated with gram-positive bacterial culture supernatants (GPCSs) after their LTA was removed or inactivated. GPCSs were obtained from three gram-positive species (pneumococci, staphylococci, and group B streptococci) during the exponential growth phase (designated early GPCSs) or at the senescent stage (designated late GPCSs). LTA was removed using an anti-LTA antibody or was inactivated by alkaline hydrolysis or platelet-activating factor acetylhydrolase (PAF-AH) treatment. Both early and late GPCSs from the three gram-positive bacteria stimulated macrophages to produce TNF-{alpha} primarily via Toll-like receptor 2 (TLR2), although late pneumococcal supernatant could stimulate macrophages via TLR4 as well. Following LTA inactivation by both methods, early GPCS lost about 85 to 100% of its activity and late GPCS lost about 50 to 90%. Both early and late culture supernatants from Escherichia coli could be inactivated by alkali hydrolysis but not by PAF-AH. In addition, removal of LTA from an early staphylococcal culture supernatant with a monoclonal antibody reduced about 70 to 85% of its potency. Reconstitution of inactivated early GPCS with a highly purified LTA restored its inflammatory activity, but the restored GPCS had higher activity than the pure LTA alone. These findings indicate that LTA is the primary TLR2 ligand in the early phase of gram-positive bacterial infection and remains a major ligand in the late phase when another TLR2 and TLR4 ligand(s) appears. In addition, our findings suggest that another gram-positive bacterial factor(s) synergizes with LTA in inducing inflammatory responses.

* Corresponding author. Mailing address: Department of Pathology, University of Alabama at Birmingham, 845 19th Street, South (BBRB-614), Birmingham AL 35294. Phone: (205) 934-0163. Fax: (205) 975-2149. E-mail: nahm{at}UAB.edu

{triangledown} Published ahead of print on 22 October 2007.

Editor: B. A. McCormick

Infection and Immunity, January 2008, p. 206-213, Vol. 76, No. 1
0019-9567/08/$08.00+0     doi:10.1128/IAI.01140-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.





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