Maturation of human humoral immunity through repeat malaria challenges

通过重复疟疾挑战使人体体液免疫成熟

• 批准号: 10720245
• 负责人: Alison Elizabeth Roth
• 金额: $ 80.12万
• 依托单位: HENRY M. JACKSON FDN FOR THE ADV MIL/MED
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-24 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10720245
• 关键词: Accounting; Address; Adult; Affinity; Animals; Antibodies; Antibody Formation; Antibody Repertoire; Antibody-mediated protection; Antigens; Appearance; Area; B-Lymphocytes; Biological Assay; Bite; Blood; CD19 gene; Cell Separation; Cells; Cessation of life; Child; Clinical; Clinical Trials; Clonal Expansion; Collaborations; Communicable Diseases; Country; Culicidae; Data; Detection; Development; Disease; Environment; Erythrocytes; Exposure to; Fever; Future; Generations; Genetic Polymorphism; Goals; Growth; Hepatocyte; Human; Humoral Immunities; Immune response; Immunity; Immunoglobulins; Immunophenotyping; In Vitro; Individual; Infection; Invaded; Legal patent; Liver; Malaria; Memory; Memory B-Lymphocyte; Micro Array Data; Modeling; Monitor; Natural Immunity; Parasite Control; Parasitemia; Parasites; Pattern; Peptides; Peripheral Blood Mononuclear Cell; Persons; Plasma; Plasma Cells; Plasmablast; Plasmodium; Plasmodium falciparum; Population; Predisposition; Production; Proliferating; Recombinants; Role; Sequence Analysis; Sorting; Sporozoites; Time; Vaccines; Virulent; Virus Diseases; Work; acquired immunity; cofactor; cytokine; design; in vitro Assay; malaria infection; multiplex assay; reduce symptoms; response; single cell sequencing; single-cell RNA sequencing; vaccine development; volunteer

Malaria continues to be among the world’s most virulent infectious diseases accounting for the death of ~0.4 million people a year. Unlike many viral infections, children usually have repeated clinical episodes, but by adulthood, the majority of individuals living in endemic areas are protected against disease, not parasite carriage. The reasons for this gradual response to the parasite are not well established. Eventually antibodies are produced in adults that reduce parasitemia and fever when passively transferred to children with malaria, indicating a role for antibody-mediated immunity. However, it has been difficult to study this slow development of immunity to natural infection in the field, since there is no way to control for parasite strain or exposure timing. Animal studies, while allowing controlled inoculations of specific parasite strains, are complicated to apply to human infections due to differences across host and parasite species. To address these limitations, we carried out a clinical trial to systematically evaluate the immune response of malaria-naïve volunteers to an initial exposure to uninfected mosquitoes, followed 2 months later with Plasmodium falciparum (Pf)-infected mosquito bites and then 2-3 subsequent challenges each with the mosquitoes infected with the same strain of Pf. The use of the controlled human malaria infection (CHMI) model allowed control of the timing of parasite exposure and therefore the early response to sequential infections could be directly monitored. As observed with children in malaria endemic countries, the initially naïve volunteers continued to be susceptible through the multiple infectious challenges, but the time to a positive blood smear, termed patency, increased significantly overtime. Symptoms decreased significantly by the 3rd and 4th challenges indicating the beginning of clinical immunity and preliminary data indicates plasma from the two subjects with the longest patency delay reduced liver cell invasion consistent with the development of pre-erythrocytic immunity. This unique, well- controlled infection model allows us to carefully follow the production of antibody-secreting plasma cells and parasite-specific memory B cells from before parasite exposure through 3 to 4 challenges with mosquitoes infected with the same strain of P. falciparum. Our preliminary analysis of the antibody repertoire of circulating plasma cells demonstrates marked clonal expansion followed by population collapse and the appearance of distinct clones. We hypothesize that B cells stimulated by the parasite proliferate and differentiate preferentially into plasma cells, not memory cells. Such a model could explain the lack of a sustained memory response to infection and subsequent delay in the acquisition of immunity. The specific aims are 1) Characterize parasite- specific memory B cell production through repeat challenges. 2) Evaluate parasite-specific memory B cells isolated after each CHMI to parasite stimulation in vitro. 3) Assess the Pf liver and blood stage growth inhibition through repeated CHMI. Together the results will advance our understanding of the memory response to Plasmodium, which is critical for the development of protective immunity.

疟疾仍然是世界上最有毒的传染病之一，其死亡约为0.4 每年有百万人。与许多病毒感染不同，儿童通常会重复临床发作，但 成年，大多数居住在内在地区的人都受到保护，而不是寄生虫 运输。这种对寄生虫的回应的原因尚未确定。最终抗体 是在成年人中生产的，这些成年人通过传递给疟疾儿童时会降低寄生虫和发烧 表明抗体介导的免疫增强作用。但是，很难研究这种缓慢的发展 由于无法控制寄生虫菌株或暴露 定时。动物研究虽然允许对特定寄生虫菌株的控制接种，但很复杂 由于宿主和寄生虫物种之间的差异，适用于人类感染。为了解决这些限制， 我们进行了一项临床试验，以系统地评估没有疟疾的志愿者的免疫响应 最初暴露于未感染的蚊子，然后在2个月后使用疟原虫（PF）感染的 蚊子叮咬，然后有2-3个随后的挑战，每个蚊子都被相同的应变感染 pf。使用受控人类疟疾感染（CHMI）模型的使用允许控制寄生虫的时机 可以直接监测暴露以及对顺序感染的早期反应。如观察到的 在疟疾内在国家的儿童中，最初的幼稚志愿者继续易受 多种感染性挑战，但阳性涂抹的时间，称为通畅，增加了 大量加班。第三和第四挑战显着改善了症状 临床免疫力和初步数据表明，这两个受试者的等离子体最长 肝细胞侵袭降低，与肉毒芽胞杆前免疫的发展一致。这个独特的，很好 受控感染模型使我们能够仔细遵循分泌抗体细胞的产生 寄生虫特异性的记忆B细胞从寄生虫暴露之前通过3至4个蚊子挑战 用相同的恶性疟原虫感染。我们对循环的抗体库的初步分析 浆细胞显示出明显的克隆扩张，随后人口崩溃和出现 不同的克隆。我们假设由寄生虫刺激的B细胞增殖并优选区分 进入浆细胞，而不是记忆细胞。这样的模型可以解释缺乏对 感染和随后的免疫获得延迟。具体目的是1）表征寄生虫 - 特定的记忆B细胞通过重复挑战产生。 2）评估寄生虫特异性记忆B细胞 在每个CHMI之后分离到体外寄生虫刺激。 3）评估PF肝脏和血液阶段抑制 通过重复的CHMI。结果共同将提高我们对记忆响应的理解 疟原虫，这对于受保护免疫的发展至关重要。