Molecular basis of immunity to tick-borne rickettsioses

蜱传立克次体病免疫的分子基础

• 批准号: 10475572
• 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
• 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/10475572
• 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; 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; Lead; Life Cycle Stages; Lipopolysaccharides; Lyme Disease; Lysosomes; 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; Vaccine Antigen; Vaccines; Variant; Virulence; Work; Yolk Sac; adaptive immune response; antibody detection; arthropod-borne; bactericide; cross reacting material 197; cross reactivity; egg; in vitro Assay; microorganism; mortality; mutant; pathogen; protective efficacy; response; spotted fever; tick bite; tick transmission; tick-borne; tick-borne pathogen; treatment choice; vaccine development; vaccine efficacy; vector

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. !

摘要 美国疾病控制和预防中心最近的一项研究显示，美国人面临着紧迫的健康危机 美国：过去一段时间被报告的壁虱传播疾病病例大幅增加 二十年了。重要的是，报告的年度发病率只占实际数量的一小部分。 被壁虱传播的病原体感染的个人。广泛的临床上重要的壁虱传播疾病 包括莱姆病、无浆体病、埃立克次体病、图拉热病、巴贝斯虫病和斑点热立克次体病。 斑点热立克次体包括立克次体(R.rickettsii，RMSF)、康氏立克次体(R.conorii) (地中海斑点热病)和帕氏立克次体(立克次体立克次体)以及许多新的 发现致病性未知的立克次体物种。多西环素被认为是 扁虱传播的立克次体病的治疗选择；然而，延误诊断和抗生素治疗可能 导致严重的疾病和死亡。寻找对侵袭性立克次体的长期免疫保护 疾病(RMSF和由R.prowazekii引起的流行性斑疹伤寒)自发现以来一直是目标 致病微生物：霍华德·T·里基茨博士。然而，全细胞减毒或福尔马林/苯酚- 灭活疫苗在人类身上产生的保护性免疫反应有限，而且由于安全 关注，不再被考虑用于立克次体疫苗的开发。我们已经开发出kkaebi转座子 诱变技术，研究立克次体细胞内生命周期(细菌)的遗传要求 附着和侵入宿主细胞，逃避内溶酶体，细胞内复制和释放 来自宿主细胞)。这项工作确定了多糖合成操纵子(PSO)负责O- 抗原的生物合成，有助于发病，并对杀菌韦尔的发展是必不可少的。 费利克斯抗体。碳水化合物结合疫苗免疫，包括荚膜多糖或 内毒素的O-抗原，产生血清特异性的保护性免疫，与 诱导杀菌抗体。这项建议旨在了解获得性免疫反应 侵袭性立克次体感染和确定立克次体O抗原结合疫苗和 针对硬质立克次体感染的保护性免疫的Weil-Felix抗体。 好了！