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: 9989476
• 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/9989476
• 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; Structure; 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 疾病控制和预防中心最近的一项研究显示， 美国：蜱传疾病报告病例数在过去显著增加 二十年重要的是，报告的年发病率仅占真实的发病率的一小部分。 感染蜱传病原体的个体。广泛的临床重要蜱传疾病 包括莱姆病、无形体病、埃立克体病、兔热病、巴贝西虫病和斑点热立克次体病。 斑点热群立克次体包括R.立克次体（Rocky Mountain Spotted Fever，RMSF）、立克次体（R.科诺里 （Mediterranean Spotted Fever）和R.帕克氏立克次体（Rickettsia parkeri rickettsiosis）以及许多新的 发现致病性未知的立克次体。强力霉素被认为是抗生素， 治疗蜱传立克次体病的选择;然而，延误诊断和抗生素治疗可 导致严重疾病和死亡。寻找抗立克次体侵袭性的长期免疫保护 疾病（RMSF和由R. prowazekii）一直是一个目标，因为发现的 致病微生物由博士霍华德T。里基茨。然而，全细胞减毒活细胞或福尔马林/苯酚- 灭活疫苗在人体内产生有限的保护性免疫应答， 不再考虑用于立克次体疫苗的开发。我们开发了kkaebi转座子 诱变技术，并研究了立克次体细胞内生活周期（细菌 附着和侵入宿主细胞，从内溶酶体逃逸，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- 抗原生物合成，有助于发病机制，是必要的发展杀菌韦尔， 菲利克斯抗体。用碳水化合物缀合物疫苗免疫，包括荚膜多糖或 脂多糖的O-抗原，产生与 杀菌抗体的诱导。该提案旨在了解适应性免疫反应， 侵袭性立克次体感染，并确定立克次体O抗原结合疫苗的作用， 针对蜱传立克次体感染的保护性免疫的Weil-Felix抗体 !