The role of natural killer cells and antibodies in protection from malaria

自然杀伤细胞和抗体在预防疟疾中的作用

• 批准号: 10571834
• 负责人: Geoffrey T Hart
• 金额: $ 51.67万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-25 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10571834
• 关键词: Ablation; Adherence; Adhesions; Affect; Antibodies; Antibody Response; Antibody-Dependent Enhancement; Antibody-mediated protection; Binding; Biological Assay; CD3 Antigens; CRISPR/Cas technology; Cause of Death; Cell Adhesion Molecules; Cell Nucleus; Cessation of life; Chondroitin Sulfate A; Clinical; Clustered Regularly Interspaced Short Palindromic Repeats; Cytokine Signaling; Data; Development; Effector Cell; Engineering; FCGR3B gene; Fc Receptor; Frequencies; Future; Granzyme; Growth; Human; Immunization; Immunize; Immunotherapy; In Vitro; Individual; Induction of Apoptosis; Infection; Invaded; Label; Malaria; Malaria Vaccines; Mediating; Membrane Proteins; Monkeys; Monoclonal Antibodies; Natural Killer Cells; Nature; Necrosis; Nitric Oxide; Parasitemia; Parasites; Placenta; Plasma; Plasmodium; Pregnancy; Pregnancy Outcome; Proliferating; Protein Isoforms; Proteins; Role; Sampling; Signal Transduction; Spontaneous abortion; Surface; System; T-Lymphocyte; Testing; Therapeutic; Therapeutic antibodies; Vaccination; Vaccine Design; Vaccines; Woman; ZAP-70 Gene; ZNF145 gene; antibody-dependent cell cytotoxicity; child bearing; cohort; cytokine; design; granulysin; human monoclonal antibodies; improved; insight; malaria infection; men; novel; perforin; placental malaria; programs; response; tool; transcription factor; vaccine efficacy

Project Summary / Abstract Malaria causes large numbers of deaths per year including 200,000 miscarriages due to placental malaria. We lack an effective malaria vaccine partially because we do not fully understand the mechanism of antibody mediated protection. Antibodies are predominantly thought to be effective through blocking mechanisms. However, we hypothesize that protective antibodies in Plasmodium infection bind infected RBC surface proteins for recognition and killing by natural killer (NK) cells. We have data showing that NK cells inhibit the growth of Plasmodium in vitro through antibody dependent cellular cytotoxicity (ADCC). We went on to show that a subset of NK cells, γ neg NK cells, have enhanced ADCC function and abundance of γ neg NK cells correlates with reduced parasitemia and protection from malaria in a large endemic malaria cohort. This proposal aims to understand how these γ neg NK cells increase function and abundance in the context of malaria infection. We will test the CD16 cascade with CRISPR/Cas9 ablations to understand why γ neg NK cells have enhanced ADCC function. We will use CRISPR/Cas9 to ablate effector and adhesion molecules to understand how NK cells inhibit the growth of Plasmodium. We will also test the underlying mechanism of malaria exposure that drives the increase in γ neg NK cells and test if γ neg NK cells expand with ADCC and malarial cytokine signals. We also aim to define NK cell ADCC protective mechanisms against the placental malaria target Var2CSA. Var2CSA is a protein on the surface of the infected RBC that adheres to the placenta and can cause miscarriages. We will test if antibodies that are good at generating NK cell ADCC responses increase with Var2CSA exposure and correlate with protective pregnancy outcomes in human and monkey samples. We will also test previously identified and novel monoclonal antibodies for NK cell ADCC function and dissect the features that generate a strong NK ADCC response. These aims in total will create a body of work that will contribute to the development of better vaccines and therapeutics for malaria. This would change vaccine targets to be proteins on the surface of infected RBCs instead of invasion proteins, predictive efficacy readouts would include NK cell ADCC assays, and antibodies developed here may be future immune therapies.

项目摘要 /摘要 疟疾每年造成大量死亡，其中包括由于疟疾的疟疾而导致的200,000人流产。我们 缺乏有效的疟疾疫苗部分，因为我们不完全了解抗体的机制 介导的保护。抗体主要被认为是通过阻断机制有效的。 但是，我们假设疟原虫感染中受保护的抗体结合了感染的RBC表面蛋白 用于自然杀手（NK）细胞的识别和杀戮。我们有数据表明NK细胞抑制了 通过抗体依赖性细胞细胞毒性（ADCC）在体外疟原虫。我们继续证明了一个子集 在NK细胞中，γ负NK细胞具有增强的ADCC功能和γ负NK细胞的抽象与 在大型流行疟疾队列中减少了寄生虫病和免受疟疾的保护。该建议旨在 了解这些γ负NK细胞如何在疟疾感染的背景下增加功能和抽象。我们 将用CRISPR/CAS9消融测试CD16级联 功能。我们将使用CRISPR/CAS9来灌溉效应子和粘合剂分子，以了解NK细胞如何抑制 疟原虫的生长。我们还将测试驱动疟疾暴露的潜在机制 γ负NK细胞的增加并测试是否随着ADCC和疟疾细胞因子信号扩展γneg NK细胞。我们也是 旨在定义NK细胞ADCC保护机制，以防止疟原虫靶标VAR2CSA。 var2csa是 感染RBC表面上的蛋白质粘附在斑点上并可能引起流产。我们将 测试随着VAR2CSA暴露和 与人和猴子样品中的保护性妊娠结局相关。我们还将测试 NK细胞ADCC功能的确定且新颖的单克隆抗体，并剖析产生A的特征 强大的NK ADCC响应。这些目标总共将创造出一大批作品，这将有助于发展 更好的疫苗和疟疾疗法。这将改变疫苗靶标为表面上的蛋白质 在感染的RBC而不是侵袭蛋白中，预测效率读数将包括NK细胞ADCC分析， 在这里开发的抗体可能是未来的免疫疗法。