Molecular basis of immunity to tick-borne rickettsioses

蜱传立克次体病免疫的分子基础

基本信息

批准号：
10686179
负责人：
Hwan Keun Kim
金额：
$ 50.42万
依托单位：
STATE UNIVERSITY NEW YORK STONY BROOK
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-01 至 2026-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10686179
关键词：
Active immunity Address Anabolism Anaplasmosis Annual Reports Antibiotic Therapy Antibiotics Antibodies Antigens Attenuated Attenuated Vaccines Babesiosis Bacteria Bacterial Attachment Site Bacterial Infections Blood Vessels Boutonneuse Fever Carbohydrates Case Study Cells Centers for Disease Control and Prevention (U.S.)Cessation of life Chemicals Clinical Conjugate Vaccines Cross Reactions Data Defect Development Diagnosis Diagnostic tests Disease Doxycycline Ehrlichiosis Endothelial Cells Enzymes Epidemic Exhibits FDA approved Formalin Generations Genes Genetic study Goals HK2 gene Habitats Health Human Immune Immune Sera Immune response Immunity Immunization In Vitro Inactivated Vaccines Incidence Individual Infection Invaded Knowledge Laboratories Life Cycle Stages Lipopolysaccharides Lyme Disease Mediating Modeling Molecular Monoclonal Antibodies Morbidity - disease rate Mus Mutagenesis O Antigens Operon Outcome Passive Immunity Pathogenesis Pathogenicity Pathology Patients Phenols Polysaccharides Preventive Proteus vulgaris Public Health Publishing Rickettsia Rickettsia Infections Rickettsia conorii Rickettsia parkeri Rickettsia prowazekii Rickettsia rickettsii Rickettsial Vaccines Rocky Mountain Spotted Fever Role Safety Serology Serotyping Subunit Vaccines Technology Testing Tick-Borne Diseases Ticks Tularemia Typhus United States Vaccines Variant Virulence Work Yolk Sac adaptive immune response antibody detection arthropod-borne bactericide chemical synthesis cross reacting material 197 cross reactivity egg in vitro Assay microorganism mortality mutant pathogen protective efficacy response spotted fever structural determinants tick bite tick transmission tick-borne tick-borne pathogen treatment choice vaccine development vaccine efficacy vector

项目摘要

ABSTRACT A recent study from the Centers for Disease Control and Prevention revealed a pressing health crisis for the United States: the number of reported cases of tick-borne diseases has increased significantly during the past two decades. Importantly, the reported annual incidence captures only a small fraction of the real number of individuals infected with tick-borne pathogens. The broad spectrum of clinically important tick-borne diseases includes Lyme disease, anaplasmosis, ehrlichiosis, tularemia, babesiosis, and Spotted Fever rickettsiosis. Spotted Fever group rickettsiae include R. rickettsii (Rocky Mountain Spotted Fever, RMSF), R. conorii (Mediterranean Spotted Fever), and R. parkeri (Rickettsia parkeri rickettsiosis) as well as many newly discovered Rickettsia species with unknown pathogenicity. Doxycycline is considered as the antibiotic of choice for the treatment of tick-borne rickettsiosis; however, delay in diagnosis and antibiotic treatment can lead to severe disease and death. The search for long-term immune protection against invasive rickettsial diseases (RMSF and epidemic typhus caused by R. prowazekii) has been a goal since the discovery of the causative microorganisms by Dr. Howard T. Ricketts. However, whole cell live-attenuated or formalin/phenol- inactivated vaccines generate limited protective immune responses in humans and, because of safety concerns, are no longer considered for rickettsial vaccine development. We have developed kkaebi transposon mutagenesis technology and studied the genetic requirements of the rickettsial intracellular life-cycle (bacterial attachment to and invasion into host cells, escape from endo-lysosome, intracellular replication, and release from host cells). This work determined that the polysaccharide synthesis operon (pso) is responsible for O- antigen biosynthesis, contributes to pathogenesis, and is essential for the development of bactericidal Weil– Felix antibodies. Immunization with carbohydrate conjugate vaccines, including the capsular polysaccharide or the O-antigen of lipopolysaccharide, generated serotype-specific protective immunity that correlated with the induction of bactericidal antibodies. This proposal aims to understand the adaptive immune responses to invasive rickettsial infections and to determine the contribution of rickettsial O-antigen conjugate vaccine and Weil–Felix antibodies toward protective immunity against tick-borne rickettsial infections. !

抽象的疾病控制与预防中心的最新研究显示美国：报告的壁虱传播病例的数量在过去有了显着增加二十年。重要的是，报告的年度事件仅捕获了实际数量的一小部分感染了tick传播病原体的人。临床上重要的tick传播疾病广泛包括莱姆病，肿瘤病，ehrllichiosis，tularemia，babesiosis和斑点发烧的立克病。 Spotted Fever组Rickettsiae包括R. Rickettsii（落基山斑点发烧，RMSF），R。Conorii （地中海斑点发烧）和R. Parkeri（Rickettsia Parkeri Rickettsiosis）以及许多新的发现具有未知致病性的人力素性物种。强力霉素被认为是选择治疗tick传播的立克氏症；但是，诊断和抗生素治疗的延迟可以导致严重的疾病和死亡。寻求对侵入性风险的长期免疫保护自从发现以来霍华德·T·里基茨博士的构造微生物。但是，整个细胞活着或福尔马林/苯酚 - 灭活的疫苗会在人类中产生有限的保护免疫反应，并且由于安全令人担忧的是不再考虑立克疫苗的开发。我们已经开发了Kkaebi Transposon 诱变技术和研究物利细胞内生命周期（细菌）的遗传要求附着在宿主细胞中并侵入，逃离内糖体，细胞内复制并释放来自宿主细胞）。这项工作确定了多糖合成歌剧（PSO）负责O- 抗原生物合成，有助于发病机理，对于细菌的发展至关重要 Felix抗体。用碳水化合物缀合物疫苗进行免疫，包括囊囊多糖或脂多糖的O-抗原，产生的血清型特异性保护性免疫，与诱导细菌抗体。该建议旨在了解适应性免疫反应侵入性立克感染并确定立克s抗原结合疫苗的贡献和 Weil – Felix抗体针对tick传播的人力体感染的保护性免疫学。呢