Enhancement of Innate Immunity Against Coxiella Pneumonia

增强针对柯克斯体肺炎的先天免疫

• 批准号: 7675558
• 负责人: Mark A Jutila
• 金额: $ 18.81万
• 依托单位: COLORADO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-01 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7675558
• 关键词: Adjuvant; Adjuvant Therapy; Agonist; Alkaloids; Antibiotics; Burkholderia; Burkholderia pseudomallei; Clinic; Collaborations; Communicable Diseases; Coxiella; Coxiella burnetii; Data; Development; Effectiveness; Genus Mycobacterium; Host Defense; Immune response; Inbred BALB C Mice; Infection; Infectious Agent; Modeling; Mus; Mycobacterium tuberculosis; Natural Immunity; Pharmaceutical Preparations; Plants; Pneumonia; Polysaccharides; Preparation; Research; Research Personnel; Research Project Grants; Resistance; Resources; Screening procedure; Testing; Therapeutic; Toll-like receptors; Vaccine Adjuvant; Vaccine Antigen; Vaccines; antimicrobial drug; biodefense; fMet-Leu-Phe receptor; immunoregulation; novel; novel vaccines; plant growth/development; programs; receptor; research clinical testing; response; vaccine efficacy

Adjuvant therapy represents a complementary approach to vaccines and conventional anti-microbial drugs as countermeasures against infectious disease. Adjuvants target and enhance innate host defenses, which have evolved over millennia to counter a wide spectrum of infectious agents. They also enhance downstream adaptive immune responses. Toll-like receptor (TLR) agonists represent the best-defined innate adjuvants, and some are under clinical testing. However, data from many studies suggest that other innate receptors may serve as alternative targets for such drugs. In ongoing adjuvant discovery programs, we have identified adjuvant activity in plant polysaccharides and alkaloids and unique synthetic compounds. In our first RCE project, we found that Coxiella burnetii i.p. infection in BALB/c mice is responsive to adjuvant therapy. In this renewal, we intend to test the effectiveness of plant derived agonists and synthetic compounds to 1) enhance innate resistance against C. burnetii infection, and 2) augment downstream adaptive immune responses against antigens and vaccine preparations." We also plan on expanding our adjuvant discovery efforts to include testing partially purified extracts of Mycobacterium tuberculosis and Burkholderia pseudomallei. The hypothesis to be tested is: Adjuvant therapy represents an effective countermeasure against C. burnetii infection. The following Specific Aims will be pursued: Specific Aim 1. Development of plant polysaccharides and alkaloids (securinine) as innate agonists to enhance innate resistance against C. burnetii infection and augment vaccine responses. Specific Aim 2. Development of novel synthetic compounds that target N-formyl peptide receptors to enhance innate resistance against C. burnetii infection and augment vaccine responses. Specific Aim 3. New adjuvant discovery focused on screening immunomodulatory compounds derived from Mycobacterium and Burkholderia. This research project fits within the RMRCE Integrated Research Focus on Immunomodulation, Adjuvants and Vaccines, and will interact directly with RP1.1 and RP1.2, and utilize the resources of Cores B, D and F. It also represents a direct collaboration between MSU and CSU investigators in efforts to identify novel adjuvant materials. Finally, this project is relevant to all infection models being pursued in the RMRCE in the context of new vaccine and/or therapeutic adjuvant discovery.

辅助治疗代表了疫苗和常规抗微生物药物的补充方法 作为对抗传染病的措施。佐剂靶向并增强宿主的先天防御， 已经进化了几千年，以对抗广泛的传染性病原体。它们还增强了 下游适应性免疫反应。Toll样受体（TLR）激动剂代表了最好定义的先天性 佐剂，有些还在临床试验中。然而，许多研究的数据表明， 受体可以作为这些药物的替代靶点。在正在进行的佐剂发现计划中，我们 在植物多糖和生物碱以及独特的合成化合物中鉴定出佐剂活性。在我们 在第一个RCE项目中，我们发现BALB/c小鼠的贝氏柯克斯体i. p.感染对佐剂 疗法在这次更新中，我们打算测试植物衍生激动剂和合成激动剂的有效性。 化合物以1）增强对C.贝氏体感染，以及2）增加下游 针对抗原和疫苗制剂的适应性免疫反应。“我们还计划扩大我们的 辅助发现工作，包括测试结核分枝杆菌的部分纯化提取物， 类鼻疽伯克霍尔德菌待检验的假设是：辅助治疗是一种有效的对策 针对C.贝氏体感染将追求以下具体目标： 具体目标1。植物多糖和生物碱（一叶秋碱）作为天然激动剂的开发， 增强对C.贝氏体感染和增强疫苗应答。 具体目标2。靶向N-甲酰肽受体的新型合成化合物的开发 增强对C.贝氏体感染和增强疫苗应答。 具体目标3。新的佐剂发现集中于筛选免疫调节化合物衍生物 分枝杆菌和伯克霍尔德氏菌 该研究项目符合RMRCE免疫调节、佐剂综合研究重点 与RP1.1和RP1.2直接相互作用，并利用核心B、D和F的资源。 它也代表了密歇根州立大学和科罗拉多州立大学研究人员之间的直接合作，以确定新的 辅助材料最后，该项目与RMRCE中正在研究的所有感染模型相关， 新疫苗和/或治疗佐剂发现的背景。