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Infect. Immun. doi:10.1128/IAI.01140-07
Copyright (c) 2007, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Lipoteichoic acid is important in innate immune responses to Gram-positive bacteria

Department of Pathology and Microbiology, University of Alabama at Birmingham, Birmingham, Alabama

^* To whom correspondence should be addressed. Email: nahm{at}UAB.edu.

	Abstract

To define the role of lipoteichoic acid (LTA) in innate immunity to Gram-positive (Gr+) bacteria, we investigated the production of TNF- by macrophages stimulated with Gr+ bacterial culture supernatants (GPCSs) after their LTA was removed or inactivated. GPCSs were obtained from three Gr+ species (pneumococci, staphylococci, and group B streptococci) during the exponential growth phase (labeled early GPCS) or at the senescent stage (labeled late GPCS). 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 GPCS from the three Gr+ bacteria stimulated macrophages to produce TNF- primarily via TLR2 although late pneumococcal supernatant could stimulate via TLR4 as well. Following both LTA inactivation methods, early GPCS lost about 85-100% of its activity and late GPCS lost about 50-90%. 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 70-85% 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 Gr+ bacterial infection and remains a major ligand in the late phase when other TLR2 and TLR4 ligand(s) appear. In addition, our findings suggest that other Gr+ bacterial factor(s) synergize with LTA in inducing inflammatory responses.