Advisory Committee Chair
Moon Nahm
Advisory Committee Members
David Briles
David Pritchard
Ken Waites
Susan Hollingshead
Suzanne Benjamine
Document Type
Dissertation
Date of Award
2008
Degree Name by School
Doctor of Philosophy (PhD) Heersink School of Medicine
Abstract
Lipoteichoic acid (LTA) is an essential bacterial membrane polysaccharide (cell wall component) that is linked to a glycerol backbone with two acyl chains. Since an antibody to LTA has been shown to protect from Gr+ bacterial infections or colonization, and the mutant Gr+ bacteria which produce less amount of LTA have less pathogenic than WT, LTA may be an important role in Gr+ bacterial infection and inflammation. The currently accepted structure of pneumococcal LTA has the pentameric repeating unit bound to the lipid anchor {Glc(β1��3)AATGal(β1��3)Glc(α1��3)-acyl2Gro}. Unlike the lipid anchor of other Gr+ bacterial LTA, this pneumococcal LTA lipid anchor has not been detected in the bacterial membrane. In addition, the current structure does not explain the Forssman antigen properties of Pneumococcal LTA. Thus we propose here the new model of pneumococcal LTA structure and show the new model has correct structure to explain its functions with a mass spectrometry. LTA can induce the production of various inflammatory molecules via Toll-like receptor 2 (TLR2) like LPS via TLR4. However, the role of LTA in Gr+ induced inflammation is still debated because there are many limitations to study LTA function. For instance, purified LTA is easily contaminated or damaged during purification step and it is impossible to make LTA-deficient Gr+ bacteria, because LTA is an essential component of Gr+ bacteria. Interestingly, its biological function can be altered by removing acyl chains because monoacylated LTA is not active in mouse model. Thus, we examined several phospholipase A2 (PLA2) to develop LTA inactivation methods. We found that PAF-acetylhydrolase, a recombinant human PLA2, is the most efficient and specific enzyme to produce monoacylated LTA that is inactive in mouse model. In early bacterial infection, Gr+ bacteria release/shed TLR2 ligands which are essential PAMPs in early infection and may be important to initiate inflammatory diseases such as sepsis. To define the molecules which are released in early stage, we identified pneumococcal molecules in the early bacteria culture supernatant with antipneumococcal antibody and we found LTA was present and may be dominant in early stage. Since LTA is potential TLR2 ligand, we hypothesis that LTA is an essential inflammatory component in early Gr+ bacterial infection. To investigate the role of LTA in early infection, three LTA inactivation methods were used to examine its role in the culture supernatants. Here we find 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. Thus, our studies have established the importance of LTA in Gr+ bacteria induced inflammation. In addition, our findings suggest that LTA is important in the early sepsis process but other components become significant in late stages of bacterial infection.
Recommended Citation
Seo, Ho Seong, "Investigation Of Lipoteichoic Acid Structure And Function To Establish Its Role In Gram-Positive Bacterial Infections" (2008). All ETDs from UAB. 3798.
https://digitalcommons.library.uab.edu/etd-collection/3798