The tick-borne Borreliae are the causative agents of relapsing fever and Lyme disease worldwide. Antibodies are the primary weapon of the mammalian immune system against both Borrelia infections. Some antibody responses have 'traditional'functions while others are more versatile and have novel functions and modes of action. A novel type of antibody to the Borrelia functions independently of the complement system in its bactericidal action, which is a unique and novel function for antibodies. The evidence for these bactericidal, complement independent antibodies is derived from both in vivo and in vitro studies. The main goal for this competitive renewal is to define the mechanism of action of the bactericidal, complement independent antibodies to Borrelia and to identify the cells that produce these antibodies. Both B. burgdorferi and relapsing fever Borreliae will be used for the experimental procedures. There is experimental evidence of colocalization of the outer surface and variable lipoproteins (Osp and Vmp) with cholesterol glycolipid domains in the outer membrane of the Borreliae. Depletion of the cholesterol leads to resistance to the bactericidal action of the antibodies. Therefore, the contribution of the Borrelia cholesterol glycolipids to the bactericidal action of the antibodies will be studied, particularly in the context of the outer membrane architecture of the antigenic determinants within the cholesterol-glycolipid domains. Imaging, structural, biophysical, and biochemical approaches will be used to determine the extent and nature of the ordered cholesterol glycolipid domains (lipid rafts) in the experiments planned for Specific Aim I. The existence of lipid rafts in a prokaryote such as Borrelia constitutes a paradigm shift in microbiology. The biogenesis of the bactericidal antibodies is the main goal of Specific Aim II. The cells that generate bactericidal antibodies can be distributed among the entire B cell repertoire. T cell independence of the bactericidal antibodies suggests the involvement of marginal zone B cells, but some of these antibodies appear to have undergone affinity maturation leading to the possibility of their being generated by other types of B cells, as well. At a time when the multiple functions of antibodies are being increasingly recognized and passive immunization is being revived as therapy for infectious and other diseases, the understanding of the versatile nature of the antibody response to Borrelia will be a significant contribution to host defense.
There are two types of infections with spirochetes of the genus Borrelia, the agents of Lyme disease, and several species of relapsing fever Borrelia. In this application, we will investigate the role of the lipids in the bactericidal action of antibodies to the Borrelia, document and characterize the lipid rafts, and determine the cell types that produce these unique antibodies.
|Huang, Zhen; Toledo, Alvaro M; Benach, Jorge L et al. (2016) Ordered Membrane Domain-Forming Properties of the Lipids of Borrelia burgdorferi. Biophys J 111:2666-2675|
|Monzón, Javier D; Atkinson, Elizabeth G; Henn, Brenna M et al. (2016) Population and Evolutionary Genomics of Amblyomma americanum, an Expanding Arthropod Disease Vector. Genome Biol Evol 8:1351-60|
|Coleman, James L; Toledo, Alvaro; Benach, Jorge L (2016) Borrelia burgdorferi?HtrA: evidence for twofold proteolysis of outer membrane protein p66. Mol Microbiol 99:135-50|
|Toledo, Alvaro; Pérez, Alberto; Coleman, James L et al. (2015) The lipid raft proteome of Borrelia burgdorferi. Proteomics 15:3662-75|
|Katona, Laura I (2015) The Fur homologue BosR requires Arg39 to activate rpoS transcription in Borrelia burgdorferi and thereby direct spirochaete infection in mice. Microbiology 161:2243-55|
|Toledo, Alvaro; Monzón, Javier D; Coleman, James L et al. (2015) Hypercholesterolemia and ApoE deficiency result in severe infection with Lyme disease and relapsing-fever Borrelia. Proc Natl Acad Sci U S A 112:5491-6|
|Toledo, Alvaro; Benach, Jorge L (2015) Hijacking and Use of Host Lipids by Intracellular Pathogens. Microbiol Spectr 3:|
|Toledo, Alvaro; Crowley, Jameson T; Coleman, James L et al. (2014) Selective association of outer surface lipoproteins with the lipid rafts of Borrelia burgdorferi. MBio 5:e00899-14|
|Coleman, James L; Crowley, Jameson T; Toledo, Alvaro M et al. (2013) The HtrA protease of Borrelia burgdorferi degrades outer membrane protein BmpD and chemotaxis phosphatase CheX. Mol Microbiol 88:619-33|
|LaRocca, Timothy J; Pathak, Priyadarshini; Chiantia, Salvatore et al. (2013) Proving lipid rafts exist: membrane domains in the prokaryote Borrelia burgdorferi have the same properties as eukaryotic lipid rafts. PLoS Pathog 9:e1003353|
Showing the most recent 10 out of 47 publications