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: 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
• 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

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