Mechanisms of antibody protection in pre-erythrocytic and blood stage malaria

红细胞前和血期疟疾的抗体保护机制

• 批准号: 8784052
• 负责人: Brandon Keith Wilder
• 金额: $ 5.15万
• 依托单位: SEATTLE BIOMEDICAL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-01 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8784052
• 关键词: Age; Animal Model; Antibodies; Antibody Formation; Antibody-mediated protection; Antigens; Attenuated; Back; Bite; Blood; Blood Circulation; C57BL/6 Mouse; CD4 Positive T Lymphocytes; CD8B1 gene; Cessation of life; Child; Clinical Research; Complement; Complex; Culicidae; Cytolysis; Data; Development; Disease; Erythrocytes; Face; Foundations; Future; Goals; Health; Hepatocyte; Human; IgG1; Immune Sera; Immune system; Immunity; Immunization; Immunoglobulin G; Immunoglobulin Variable Region; Inbred BALB C Mice; Infection; Infection Control; Infection prevention; Intravenous; Invaded; Investigation; Knowledge; Laboratories; Life; Life Cycle Stages; Liver; Malaria; Malaria Vaccines; Mediating; Membrane Proteins; Modeling; Monitor; Monoclonal Antibodies; Mus; Parasite Control; Parasitemia; Parasites; Pharmaceutical Preparations; Phase; Phase III Clinical Trials; Plasmodium; Play; Point Mutation; Production; Prophylactic treatment; Proteins; Radiation; Rodent Model; Role; Serum; Skin; Sporozoites; Staging; Sterility; Subunit Vaccines; T-Lymphocyte; Time; Vaccine Design; Vaccines; base; burden of illness; cell motility; circumsporozoite protein; design; improved; in vivo; killings; liver infection; mutant; next generation; pathogen; polyclonal antibody; preclinical study; public health relevance; receptor; receptor binding; research study; response; sample fixation; tool; transmission process; vaccine development; vector mosquito

DESCRIPTION (provided by applicant): Infections with Plasmodium parasites, the causative agents of malaria, constitute one of the world's largest disease burdens with up to 300 million infections and 1.2 million deaths each year. The parasite maintains an incredibly complex life cycle between mosquito vector and mammalian host. After transmission, it will pass through the skin and bloodstream as sporozoites, which infect liver hepatocytes, then develops as liver stages and emerges back into the blood as red blood cell-infective merozoites. The pre-erythrocytic (sporozoites and liver stages) phase is an ideal target for vaccine development as it is asymptomatic and has limited parasite numbers. However, as only one parasite can cause a fulminant blood stage infection, preventing blood stage disease with pre-erythrocytic immunity faces a challenge. Immunization with attenuated parasites which invade and infect the liver but fail to progress to blood stage have been highly effective in preclinical and clinical studies. The conventional understanding is that this protection relies predominantly by CD8+ T cells. However, I have shown that both monoclonal antibodies (mAb) against the sporozoite protein CSP and polyclonal antibodies (pAb) elicited by immunization with whole parasites are capable of providing robust protection against an infectious mosquito bite. The Abs elicited by whole parasite immunization (WPI) can also control a direct blood stage infection independent of T cell help. Little is known about the antibody effector mechanisms mediating this protection at either stage, but the cross-stage protection afforded by WPI provides an ideal platform on which to investigate these mechanisms. I propose to use this model to investigate the contributions of neutralization, complement-mediated lysis and opsonization underlying Ab-mediated protection in a rodent model of malaria. Aim 1 will focus on protection against sporozoite infection by passive transfer of mutant mAb which lack specific FC-mediated effector functions. These mutant mAb will be compared to WT mAb for their ability to reduce liver stage burden following infection by mosquito bite. Furthermore, passive transfer of WPI serum followed by mosquito bite challenge in mice deficient in complement, FC receptor binding or both will elucidate the role of each mechanism in the context of WPI. Aim 2 will expand this model to examine antibody-mediated protection in the blood stage of disease. Again, passive transfer of WPI serum to mice deficient in complement, FC receptor binding or both will be followed by direct blood stage challenge. By monitoring subsequent parasitemia, we will be able to determine the respective contributions (if any) of each effector mechanism to control of blood stage malaria. The studies proposed here represent the first comprehensive and exhaustive analysis of the mechanisms conferring antibody-mediated protection against both the sporozoite and blood stages of Plasmodium. Knowledge of the specific type of antibody response required for effective protection at these stages will guide the rational design of the next generation of malaria vaccines aimed at preventing infection.

描述（由申请人提供）：疟原虫寄生虫（疟疾的病原体）感染是世界上最大的疾病负担之一，每年有多达3亿人感染，120万人死亡。这种寄生虫在蚊子载体和哺乳动物宿主之间维持着令人难以置信的复杂生命周期。传播后，它将通过皮肤和血液作为子孢子，感染肝细胞，然后发展为肝阶段，并作为红细胞感染裂殖子出现回到血液中。红细胞前期（子孢子和肝脏阶段）是疫苗开发的理想目标，因为它是无症状的，寄生虫数量有限。然而，由于只有一种寄生虫可以引起暴发性血液期感染，因此用红细胞前免疫预防血液期疾病面临挑战。在临床前和临床研究中，用侵入并感染肝脏但不能进展到血液阶段的减毒寄生虫进行免疫是非常有效的。的 传统的理解是，这种保护主要依赖于CD8+ T细胞。然而，我已经表明，针对子孢子蛋白CSP的单克隆抗体（mAb）和通过用整个寄生虫免疫引起的多克隆抗体（pAb）都能够提供针对感染性蚊子叮咬的强大保护。由全寄生虫免疫（WPI）引起的Ab也可以控制不依赖于T细胞帮助的直接血液阶段感染。关于在任一阶段介导这种保护的抗体效应机制知之甚少，但WPI提供的跨阶段保护提供了研究这些机制的理想平台。我建议使用这个模型来研究啮齿动物疟疾模型中中和、补体介导的溶解和调理作用对Ab介导的保护作用的贡献。目的1是研究缺乏特异性FC介导效应子功能的突变型单克隆抗体的被动转移对子孢子感染的保护作用。将这些突变mAb与WT mAb比较其减少蚊子叮咬感染后肝脏阶段负荷的能力。此外，WPI血清的被动转移，随后在补体、FC受体结合或两者缺陷的小鼠中进行蚊子叮咬攻击，将阐明WPI背景下每种机制的作用。目的2将扩展该模型以检查疾病血液阶段中抗体介导的保护。同样，将WPI血清被动转移至补体、FC受体结合或两者缺陷的小鼠后，将进行直接血液阶段激发。通过监测随后的寄生虫血症，我们将能够确定每个效应机制对控制血液期疟疾的各自贡献（如果有的话）。这里提出的研究代表了第一个全面和详尽的分析机制，赋予抗体介导的保护，对疟原虫的子孢子和血液阶段。了解这些阶段有效保护所需的特定抗体反应类型，将指导旨在预防感染的下一代疟疾疫苗的合理设计。