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.

项目摘要/摘要 需要高效的疫苗来帮助控制疟疾的全球疾病燃烧。候选疫苗 靶向疟疾的肝脏阶段在未经疟疾的人类中试验时表现出了有希望的效率，但是 在目标人群中接受疟疾疫苗的测试时表现令人失望：患有疟疾的个体 - 内在区域。血阶段疟疾会产生潜水的免疫抑制作用，其中有些超过了 清除感染。该提案使用鼠模型来探讨血液阶段疟疾的假设 感染会在宿主免疫环境中产生持久的改变，以防止未来的免疫 生成最佳保护的响应。在一种新型的鼠感染 - 免疫 - 回报模型中 为了解决这个主题而开发的，辐射衰减的孢子菌的免疫抑制作用较低 与没有血液阶段的比较剂相比，具有血阶段疟疾史的小鼠的保护。 拟议的工作使用一系列实验可牵引的小鼠模型来剖析机械基础 AIM 1将测试是否 寄生虫产生的血红蛋白衍生物是观察到的免疫抑制反应受损的关键驱动力 解决血液阶段疟疾后。 AIM 2将确定是否由于 抗原表现的减少解释了小鼠血液期疟疾史的反应不良 免疫。 该项目旨在简单地提高疟疾免疫力并准备 通过进口潜水员来进行疟疾发病机理和免疫力的进一步独立研究 疟疾的免疫学和啮齿动物模型的方法。