Targeted Prevention of Human Ehrlichiosis

人类埃利希体病的针对性预防

• 批准号: 10667509
• 负责人: YASUKO RIKIHISA
• 金额: $ 39.38万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-17 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10667509
• 关键词: Adverse effects; Amblyomma; Anaplasma; Animal Model; Anti-Infective Agents; Antibiotics; Antibodies; Antibody Response; Apoptosis; Autophagocytosis; Bacteria; Binding; Blood Transfusion; Canis familiaris; Cells; Centers for Disease Control and Prevention (U.S.); Cessation of life; Cloning; Combined Vaccines; Country; DNA Sequence; DNA Vaccines; Data; Development; Doxycycline; Ehrlichia; Ehrlichia chaffeensis; Ehrlichiosis; Emerging Communicable Diseases; Exposure to; FDA approved; Formulation; Future; Genetic Transcription; Geographic Locations; Goals; Growth; High Prevalence; Human; Immune response; Immunization; Immunize; Incidence; Infection; Infectious Agent; Interferon Type II; Jet Injections; Learning; Life; Lipoproteins; Mammalian Cell; Mammals; Measures; Mediating; Membrane Proteins; Methods; Military Personnel; Mission; Mus; Needles; Nutrient; Outcome; Pilum; Police; Predisposition; Prevention; Process; Proteins; Public Health; Publishing; Receptor Cell; Recombinants; Reporting; Rickettsia; Rickettsia Infections; Risk; Sentinel; Surface; Symptoms; T cell response; T-Lymphocyte; Testing; Th1 Cells; Tick-Borne Diseases; Ticks; Toxic effect; Type IV Secretion System Pathway; United States National Institutes of Health; VDAC1 gene; Vaccines; Vector-transmitted infectious disease; Wild Animals; Work; Zoonoses; cell mediated immune response; disability; evidence base; expression vector; flu; geographic risk; high risk; improved; knowledge translation; large scale production; monocyte; mortality; neutralizing antibody; pathogen; plasmid DNA; prevent; prophylactic; response; tick bite; tick transmission; tick-borne; tick-borne pathogen; transmission blocking; transmission process; vaccine candidate; vaccine delivery; vaccine development

The incidence of tick-borne diseases has risen dramatically in the past two decades, and continues to rise. Human monocytic ehrlichiosis caused by Ehrlichia chaffeensis (Ech) is one of the most prevalent, life- threatening, emerging tick-borne zoonoses in the US. Ech is an obligatory intracellular bacterium of the order Rickettsiales. Therapy of choice is the broad-spectrum antibiotic doxycycline, which is effective only if initiated early. Currently there is no FDA-approved vaccine for Ech. Our long-term goal is to develop an evidence- based vaccine approach to effectively protect humans by targeting multiple critical steps of the rickettsial infection cycle. Toward this goal, we identified four Ech surface-exposed proteins that have known functions required for Ech survival, and that also lack homology to human proteins, OMP-1/P28, Entry triggering protein of Ehrlichia (EtpE), and VirB2. OMP-1/P28s are immunodominant surface-exposed outer membrane proteins that have porin activity essential for bacterial nutrient acquisition. P28 and OMP-1B are predominantly expressed in mammals and ticks, respectively. EtpE is an invasin that uses its C-terminus (EtpE-C) to bind the host cell receptor to trigger Ech entry. We have shown that the type IV secretion system (T4SS) is essential for Ech survival within the host cell. VirB2 is a T4SS pilus protein that is part of the T4SS machinery. Immunization of mice with recombinant P28, EtpE, or VirB2 proteins generated Ech-specific antibody responses that prevented Ech infection. These data support our premise that these proteins serve as rational vaccine candidates for targeting non-overlapping processes in Ech infection of mammalian host cells. DNA vaccines offer a number of potential advantages over traditional vaccines, including the stimulation of both humoral and T-cell-mediated responses, improved vaccine stability, the absence of any infectious agent, and the relative ease of packaging multi-components and large-scale manufacture. We showed the feasibility of an Ech DNA vaccine in dogs by safely immunizing dogs with the DNA vaccines by percutaneous needle-free jet injection and demonstrating humoral and cell-mediated immune responses to the DNA vaccines. Our hypothesis is immunization with plasmid DNA vaccine encoding P28, OMP-1B, EtpE and VirB2 singly or in combination prevents Ech transmission from ticks to mammals. To test this hypothesis, our Specific Aims are: 1. To construct DNA vaccines encoding P28, OMP-1B, EtpE-C, and VirB2, determine the development of humoral and cell-mediated immune responses in immunized mice, and evaluate protection of immunized mice from infection with Ech cultured in tick cells. 2. To test if immunization of dogs with P28, OMP-1B, EtpE-C and VirB2 can prevent Ech transmission from infected ticks. The immediate outcomes of the proposed studies will be to provide proof-of-principle for a DNA vaccine approach to the Ech vaccine candidates for blocking of Ech transmission from ticks to dogs. The long-term outcome will be development of an anti-infective vaccine against HME in humans that does not cause adverse effects.

在过去二十年中，蜱传疾病的发病率急剧上升，而且还在继续上升。