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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

基本信息

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
项目类别：
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

项目摘要

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