Molecular Patterns of Borrelia - Chemical Structure and Innate Immune Responses involving LPS Binding Protein (LBP)

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The object of this study is to define the molecular mechanisms of the induction of innate immune responses induced by glycolipids isolated from the outer membrane of spirochetes including Treponema, Borrelia and Leptospira. Following chemical characterization, we will perform structure-function analysis of cellular host responses via Toll-like receptors (TLRs). Defining structural elements of spirochetal glycolipids required for biological activity should lead to the definition of molecular patterns of bacterial compounds essential for stimulation of innate immune responses in general. In previous work, we isolated glycolipids of the outer membrane of two treponeme strains, and chemical analysis revealed a structure closely related to Lipoteichoic acid (LTA) of Gram-positive bacteria. These compounds induced cytokine release in mono- nuclear cells depending on Lipopolysccharide (LPS) binding protein (LBP), CD14 and TLRs. Based on these findings, the proposed project extends this work to clinically highly relevant spirochetes including B. burgdorferi. Chemical analysis will be performed in close collaboration with the Borstel Research Center followed by stimulation experiments using cell lines transfected with different TLRs established in our lab. This will be completed by studies on TLR-deficient mice, and clinical investigations on the role of TLR-polymorphisms in Lyme disease. Defining the molecular patterns required for innate immune responses may aid in developing novel prevention and intervention strategies in infectious caused by spirochetes and other bacteria.