A novel antimicrobial resistance mechanism for Borrelia burgdorferi

伯氏疏螺旋体的新型抗菌药物耐药机制

• 批准号: 10425475
• 负责人: JON T SKARE
• 金额: $ 22.73万
• 依托单位: TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10425475
• 关键词: Address; Affect; Aftercare; Antibiotic Therapy; Antimicrobial Cationic Peptides; Antimicrobial Resistance; Area; Arthropods; Bacteria; Bacteria sigma factor KatF protein; Binding; Binding Proteins; Biochemical; Bite; Borrelia; Borrelia burgdorferi; Borrelia oxidative stress regulator; Cell Line; Cell membrane; Cells; Complement; Data; Databases; Dermal; Dermis; Diagnosis; Environment; Etiology; Family member; Fibroblasts; Foundations; Gene Proteins; Genes; Growth; Homologous Gene; Human; Immune; Immune response; In Vitro; Infection; Ixodes; Knock-in; Knowledge; Length; Ligands; Locales; Lyme Disease; Maintenance; Mammals; Mediating; Membrane; Membrane Proteins; Methods; Morbidity - disease rate; Natural Immunity; Order Spirochaetales; OspC protein; Parents; Pathogenesis; Pathogenicity; Patients; Peptides; Persons; Poison; Predisposition; Primary Infection; Production; Property; Proteins; Recombinants; Reporting; Role; Seminal; Skin; Skin colonization; Structure; Surface; Surface Plasmon Resonance; Syndrome; System; Testing; Time; Tissues; United States; Vertebrates; Virulence; Work; adaptive immune response; adaptive immunity; antimicrobial peptide; base; cell killing; dermcidin; enzootic; extracellular; gain of function; immune clearance; insight; intercalation; interest; knowledge base; mutant; novel; pathogen; prevent; protein function; resistance mechanism; tick feeding; tick transmission; transmission process

PROJECT SUMMARY The etiologic agent of Lyme disease, Borreliella burgdorferi, is a spirochetal bacterium that represents the most common arthropod-based infection in the United States. Each year Lyme disease contributes to significant morbidity in patients within endemic areas as well as for those who suffer from post treatment Lyme disease syndrome. B. burgdorferi is considered an extracellular pathogen and, as such, must contend with the host response to colonize and persist in the face of active innate and adaptive immunity. Prior studies demonstrated that conditions mimicking mammalian infection induce the expression of BosR/RpoN/RpoS-regulated virulence associated B. burgdorferi genes, including ospC, dbpBA, and bbk32. In addition to these genes, other loci that are coordinately regulated have been identified but the proteins they encode have no known function(s). Many groups, including the Skare and Höök labs, have focused on surface exposed proteins to determine how they interface with host structures to promote the pathogenic potential of B. burgdorferi. One limitation in determining function is the lack of homology that these borrelial proteins share with virulence associated proteins from other pathogens. The dearth of information of how these surface exposed proteins contribute to the establishment and maintenance of B. burgdorferi infectivity and pathogenesis represents a significant gap in the current knowledge base. One such borrelial gene/protein that fits this description is bbk53/BBK53 and its paralogues. Preliminary data presented herein indicates that recombinant BBK53 binds to human dermcidin (hDCD), an anionic antimicrobial peptide that is produced by dermal fibroblasts. Subsequently, the Skare and Höök groups found that B. burgdorferi lacking bbk53 were more sensitive to hDCD relative to its isogenic parent and complement strains. These results suggest that B. burgdorferi BBK53 binds to hDCD and prevents the integration of this lethal peptide into borrelial membranes, most notably the energized cytoplasmic membrane, and thus reduces innate killing of these spirochetes during initial infection within the skin. This hypothesis will be tested with the following Specific Aims: (1) Characterize the interactions between BBK53::hDCD and hDCD derivatives; and (2) Determine if BBK53 provides an hDCD-dependent survival advantage to B. burgdorferi following in vitro infection. The role described here for BBK53 is significant as it represents the first anionic antimicrobial peptide resistance mechanism observed for B. burgdorferi. As such, BBK53 may reduce innate clearance of B. burgdorferi, promote colonization of the skin, and provide a larger pool of spirochetes for subsequent dissemination into deeper tissues.

项目总结