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）：疟原虫寄生虫的感染，疟疾的病因，构成了世界上最大的疾病负担之一，每年高达3亿次感染和120万死亡。该寄生虫在蚊子和哺乳动物宿主之间保持了一个非常复杂的生命周期。传播后，它将以孢子虫的形式穿过皮肤和血液，后者感染肝肝细胞，然后随着肝脏阶段而发育，并以红细胞对感染的默罗物的形式出现，并回到血液中。肉毒前（子孢子和肝脏阶段）相是疫苗发育的理想目标，因为它是无症状的，并且寄生虫数量有限。但是，由于只有一个寄生虫会引起暴发性血液阶段感染，从而防止血液中的免疫疾病面临挑战。侵入和感染肝脏但未能进入血液的降低寄生虫的免疫接种在临床前和临床研究中非常有效。这 常规的理解是，这种保护主要取决于CD8+ T细胞。但是，我已经表明，两种单克隆抗体（MAB）针对孢子岩蛋白CSP和多克隆抗体（PAB）（通过整个寄生虫）引起的多克隆抗体（PAB），能够为感染性蚊子提供强大的保护。整个寄生虫免疫（WPI）引起的ABS还可以控制与T细胞帮助无关的直接血液阶段感染。关于在任何一个阶段介导这种保护的抗体效应机制知之甚少，但是WPI提供的跨阶段保护提供了研究这些机制的理想平台。我建议使用该模型研究中和，补体介导的裂解和打击在疟疾啮齿动物模型中的基础AB介导的保护。 AIM 1将通过被动转移突变mAB的被动转移，而该效应器功能的被动转移将重点放在防孢子虫感染上。这些突变的mAb将与WT MAB进行比较，以减轻蚊子叮咬感染后肝脏阶段负担的能力。此外，在缺乏补体，FC受体结合的小鼠中，WPI血清的被动转移，然后是蚊子咬合挑战，或者两者都会阐明每种机制在WPI背景下的作用。 AIM 2将扩大该模型，以检查疾病血液中抗体介导的保护。同样，将WPI血清的被动转移向缺乏补体，FC受体结合或两者的小鼠进行直接血液阶段挑战。通过监测随后的寄生虫血症，我们将能够确定每个效应子机制的各自贡献（如果有）控制血液期疟疾。此处提出的研究代表了对抗体介导的对疟原虫的孢子岩和血液阶段赋予抗体介导的保护的机制的首次全面和详尽的分析。了解在这些阶段有效保护所需的特定抗体反应类型的知识将指导旨在防止感染的下一代疟疾疫苗的合理设计。