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. !

抽象的美国疾病控制与预防中心最近的一项研究揭示了紧迫的健康危机美国：过去蜱传疾病报告病例数大幅增加重要的是，报告的年发病率仅占真实数量的一小部分。感染蜱传病原体的个体临床上重要的蜱传疾病的广谱。包括莱姆病、无形体病、埃立克体病、兔热病、巴贝斯虫病和斑点热立克次体病。斑点热群立克次体包括立克次氏体（落基山斑疹热，RMSF）、康氏立克次体（地中海斑疹热）、帕克里立克次体（帕克里立克次体）以及许多新发现的发现的致病性未知的立克次体物种，强力霉素被认为是抗生素。蜱传立克次体病的治疗选择；然而，诊断和抗生素治疗的延误可能会导致导致严重疾病和死亡。寻找针对侵袭性立克次体的长期免疫保护。自从发现 R. prowazekii 以来，疾病（RMSF 和由 R. prowazekii 引起的流行性斑疹伤寒）一直是一个目标然而，全细胞减毒活病毒或福尔马林/苯酚- 致病微生物。灭活疫苗对人类产生有限的保护性免疫反应，并且由于安全性立克次体疫苗的开发不再考虑这些问题，我们已经开发了 kkaebi 转座子。诱变技术并研究了立克次体细胞内生命周期（细菌附着和侵入宿主细胞、逃离内溶酶体、细胞内复制和释放这项工作确定了多糖合成操纵子 (pso) 负责 O-。抗原生物合成，有助于发病机制，对于杀菌 Weil 的发展至关重要- 使用碳水化合物结合疫苗（包括荚膜多糖或）进行免疫。脂多糖的 O 抗原，产生与该提案旨在了解杀菌抗体的适应性免疫反应。侵袭性立克次体感染并确定立克次体 O 抗原结合疫苗的贡献和针对蜱传立克次体感染的保护性免疫的韦尔-菲利克斯抗体。！