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

Abstract

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-␣) 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-␣ 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.

Divergent roles of Toll‐like receptor 2 in response to lipoteichoic acid and Staphylococcus aureus in vivo

“…This ligand is shed from the bacteria and is responsible for the proinflammatory response generated by bacterial culture supernatants within the first 4 h of inoculation [27]. We found a key role for IFN-g-primed nonhematopoietic cells in driving leukocyte recruitment in response to local administration of LTA in the microvasculature.…”

Lactobacillus plantarum Lipoteichoic Acid Alleviates TNF-α-Induced Inflammation in the HT-29 Intestinal Epithelial Cell Line

“…It also causes septic shock and multiorgan failure (Bougarn et al, 2010;De Kimpe et al, 1995;Knapp et al, 2008;Rainard et al, 2008;Yang et al, 2009). LTA plays important roles in both innate and adaptive immunity (Chan et al, 2007;Kim et al, 2007b;Seo et al, 2008). Although precise mechanical differences have not yet been reported, LTAs have differential immunostimulatory effects on host cells according to origin.…”

Evidence for the detection of non-endotoxin pyrogens by the whole blood monocyte activation test

“…ltA and lipoproteins are recognized via toll-like receptors (tlR) 2/6 or tlR2/tlR1 (Jin et al, 2007). Some groups report that peptidoglycan, lipoproteins or ltA play a central role in immune activation (Bubeck Wardenburg et al, 2006;Hoebe et al, 2005;Seo et al, 2008;Boneca, 2005;Dziarski and Gupta, 2005;lien et al, 1999;Morath et al, 2005, while their ability to induce cytokine release is questioned by others (Hashimoto et al, 2006;travassos et al, 2004). the core of the discussion is how pure the preparations being tested are and whether minor contaminations with the other components of the cell wall are in fact responsible for immune activation.…”