Dissecting compromised efficacy of liver-stage malaria immunizations in hosts with a history of blood-stage malaria

剖析有血期疟疾史的宿主肝期疟疾免疫效果受损

• 批准号: 10533975
• 负责人: Lisa L Drewry
• 金额: $ 2.62万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-28 至 2022-12-02
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10533975
• 关键词: Activities of Daily Living; Address; Antigen Presentation; Antigen-Presenting Cells; Antigens; Antimalarials; Area; Attenuated; Blood; CD11c Antigens; CD8-Positive T-Lymphocytes; Cell Compartmentation; Cessation of life; Clinical Trials; Complement; Data; Defect; Disease; Environment; Future; Goals; Hemoglobin; Hepatocyte; Human; Immune; Immunity; Immunization; Immunologics; Immunology; Immunosuppression; Impairment; In Vitro; Individual; Infection; Inferior; Inflammasome; Injections; Knowledge; Lead; Liver; Malaria; Malaria Vaccines; Modeling; Molecular; Morbidity - disease rate; Mus; National Institute of Allergy and Infectious Disease; Parasites; Parasitology; Pathogenesis; Pathway interactions; Phase II/III Trial; Phenotype; Population; Populations at Risk; Process; Production; Radiation; Recording of previous events; Research; Research Personnel; Resolution; Rodent Model; Role; Series; Sporozoites; T cell response; Target Populations; Testing; Training; Transgenic Organisms; Vaccines; Work; adaptive immune response; adaptive immunity; base; burden of illness; design; draining lymph node; experience; hemozoin; high risk; immunogenic; in vivo; knowledge base; malaria infection; migration; mouse model; novel; prevent; programs; protective efficacy; radiation response; recruit; response; trafficking; vaccine candidate; vaccine efficacy; vaccine trial

PROJECT SUMMARY/ABSTRACT Highly effective vaccines are needed to help control the global disease burden of malaria. Candidate vaccines targeting the liver-stage of malaria have shown promising efficacy when trialed in malaria-naïve humans, but performed disappointingly when tested in the target population for malaria vaccines: individuals living malaria- endemic regions. Blood-stage malaria produces diverse immunosuppressive effects, some of which outlast the clearance of infection. This proposal uses a murine model to explore the hypothesis that blood-stage malaria infections produce lasting alterations in the host immune environment that prevent future immunizations from generating optimally protective responses. In a novel murine infection-immunization-rechallenge model developed to address this topic, immunization with radiation-attenuated malaria sporozoites produced inferior protection in mice with a history of blood-stage malaria, compared to blood-stage-naïve comparators. The proposed work uses a series of experimentally tractable mouse models to dissect the mechanistic basis of compromised immunization efficacy in hosts with a history of blood-stage malaria. Aim 1 will test whether a parasite-produced hemoglobin derivative is a key driver of the impaired immunization responses observed after resolution of blood-stage malaria. Aim 2 will determine whether ineffective CD8 T-cell priming due to reductions in antigen presentation explains the poor responses of mice with a history of blood stage malaria to immunization. This project is designed to simultaneously advance knowledge of malaria immunity and prepare the investigator for further independent research in malaria pathogenesis and immunity by incorporating diverse approaches in immunology and rodent models of malaria.

项目总结/摘要 需要高效疫苗来帮助控制疟疾的全球疾病负担。候选疫苗 针对疟疾肝脏阶段的药物在疟疾初治人群中试验时显示出有希望的疗效，但 在疟疾疫苗的目标人群中进行测试时，表现令人失望： 地方病流行区。血液阶段的疟疾产生不同的免疫抑制作用，其中一些持续时间超过 清除感染。这项提议使用小鼠模型来探索血液阶段疟疾 感染在宿主免疫环境中产生持久的改变，从而阻止未来的免疫接种， 产生最佳的保护性反应。在一种新的小鼠感染-免疫-再激发模型中， 为了解决这个问题，用放射减毒的疟疾子孢子进行免疫接种， 在有血液期疟疾史的小鼠中的保护作用，与血液期初治的对照组相比。的 拟议的工作使用一系列实验上易于处理的小鼠模型来剖析 在有血液期疟疾病史的宿主中，免疫效力会受到影响。目标1将测试 寄生虫产生的血红蛋白衍生物是观察到的免疫应答受损的关键驱动因素 在血液阶段疟疾消退后。目的2将确定是否由于免疫缺陷而导致无效的CD 8 T细胞引发。 抗原呈递的减少解释了具有血液期疟疾史的小鼠对 次免疫 该项目旨在同时提高疟疾免疫知识并准备 研究人员通过整合各种不同方法， 免疫学方法和疟疾的啮齿动物模型。