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Virulence Mechanisms of Multifunctional Borrelial Proteins

多功能疏螺旋体蛋白的毒力机制

基本信息

批准号：
10192642
负责人：
Brandon Lee Garcia
金额：
$ 73.11万
依托单位：
EAST CAROLINA UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-06-15 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10192642
关键词：
Address Affinity Amino Acids Animal Model Antibodies Asia Bacteria Binding Biochemical Biological Assay Biophysics Borrelia Borrelia Infections Borrelia afzelii Borrelia burgdorferi Borrelia burgdorferi Group Borrelia garinii Borrelia miyamotoi Borrelia turicatae Classical Complement Pathway Clinical Communicable Diseases Complement Complement 1q Complement Activation Complement component C1r Complex Crystallization Cytolysis Data Disease Disease model Etiology Europe Event Experimental Models Family Genes Genetic Goals Hematogenous Homologous Gene Hot Spot Human Immune Immunity Immunocompetent Immunomodulators Impairment In Vitro Infection Lipoproteins Lyme Disease Lytic Measures Mediating Medical Microbe Microbiology Minor Modeling Molecular Mus Natural Immunity Nature Order Spirochaetales Orthologous Gene Pathogenesis Pathway interactions Pattern Recognition Peptide Hydrolases Phenotype Phylogenetic Analysis Play Proteins Reaction Relapsing Fever Reporting Resolution Role Serum Spirochaetales Infections Structure Surface Testing Ticks United States Vector-transmitted infectious disease Virulence X-Ray Crystallography arm biophysical techniques complement pathway complement system design experimental study human disease imaging approach immunoregulation in vitro activity in vivo in vivo Model in vivo imaging inhibitor/antagonist interdisciplinary approach lyme pathogenesis mouse model multidisciplinary mutant pathogen relapsing fever borrelia tick borne spirochete vector-borne vector-borne pathogen

项目摘要

PROJECT SUMMARY Spirochetes of the Borrelia genus are the cause of several prevalent vector-borne diseases. The most well-known pathogen from this group is Borrelia burgdorferi sensu stricto, which causes over 300,000 cases of Lyme disease in the United States each year. B. garinii and B. afzelii, which belong to the B. burgdorferi sensu lato complex, are the primary agent of Lyme disease in Europe and Asia. Borrelia spirochetes are also the etiological agent of the ancient human disease relapsing fever, as well as a newly recognized infectious condition called Borrelia miyamotoi disease. Lyme-associated, relapsing fever-associated, and B. miyamotoi spirochetes have differing lifecycles and their infections are accompanied by distinct clinical presentations. However, each of these pathogens are known to encode multifunctional surface-expressed lipoproteins that interact with vertebrate host molecules. Among these proteins are a small arsenal of immunomodulators that specifically target and inactivate a primary arm of innate immunity known as the complement system. We have recently reported two independent lines of evidence that support the hypothesis that one of these pathways, known as the classical pathway, is important in controlling B. burgdorferi infections. First, we have shown that mice deficient in the pattern recognition molecule of the classical pathway, C1q, are significantly more susceptible to B. burgdorferi infection. Secondly, we have shown that the lipoprotein B. burgdorferi BBK32 is a high-affinity inhibitor of the initiating protease of the classical pathway, C1r. In Aim 1 of this project we seek to understand the C1r inhibitory activity of BBK32 sensu lato proteins at the molecular level. In Aim 2 we will determine the immunomodulatory roles and virulence contribution of three BBK32 orthologues known as FbpA, FbpB, and FbpC which are found uniquely in relapsing fever and B. miyamotoi spirochetes. In Aim 3 we will delineate the role of C1r inhibition in borrelial pathogenesis using in vivo models of disease. To achieve this, we propose a multi-disciplinary strategy that employs x-ray crystallography, biophysical approaches, and complement functional assays to pinpoint key ‘hot-spot’ residues on BBK32 that give rise to its potent anti-C1r activity. These data will inform the design of bbk32 mutants which will be used in mouse infectivity studies to connect structural features of BBK32, at the amino-acid level, to an in vivo phenotype. Parallel studies will use genetic deletion mutants of fbp genes from the relapsing fever- associated spirochetes B. turicatae and B. hermsii. These studies will be paired with experimental models of Lyme and relapsing fever borrelioses using C1r-/- mice to better understand the role of the classical pathway initiating protease in the control of borrelial infections. By addressing fundamental questions of how medically important Borrelia spirochetes recognize and evade host immunity, the studies proposed here stand to have a broad and significant impact on the field of bacterial pathogenesis.

项目总结