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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/摘要需要高效的疫苗来帮助控制疟疾的全球疾病负担。在未患疟疾的人类身上进行试验时，针对疟疾肝脏阶段的药物显示出有希望的功效，但是在目标人群中进行疟疾疫苗测试时，结果令人失望：患有疟疾的个人血期疟疾会产生多种免疫抑制作用，其中一些作用比流行期更持久。该提案使用小鼠模型来探索血液阶段疟疾的假设。感染会对宿主免疫环境产生持久的改变，从而阻止未来的免疫接种在新型小鼠感染-免疫-再攻击模型中产生最佳保护反应。为解决这一主题而开发的，用辐射减弱的疟疾子孢子进行免疫产生的效果较差与未接触过血期疟疾的小鼠相比，对有血期疟疾病史的小鼠具有保护作用。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其机制基础有血期疟疾病史的宿主的免疫效果受损目标 1 将测试是否存在。寄生虫产生的血红蛋白衍生物是观察到的免疫反应受损的关键驱动因素血期疟疾解决后，目标 2 将确定 CD8 T 细胞启动是否无效。抗原呈递的减少解释了有血期疟疾病史的小鼠对疟疾反应不佳的原因免疫接种。该项目旨在同时增进疟疾免疫知识并为疟疾免疫做好准备研究者通过整合不同的方法对疟疾发病机制和免疫进行进一步的独立研究免疫学和疟疾啮齿动物模型的方法。