Antigen Discovery and Vaccine Development for Human Babesia Parasites

人类巴贝虫寄生虫的抗原发现和疫苗开发

• 批准号: 10386919
• 负责人: CHOUKRI BEN MAMOUN
• 金额: $ 41.88万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-13 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10386919
• 关键词: Adjuvant; Antibodies; Antigens; Babesia; Babesia microti; Babesiosis; Biological; Biology; Black-legged Tick; Blood; Blood Transfusion; Borrelia microti; California; Case Fatality Rates; Case Study; Cell membrane; Cells; Cellular biology; Centers for Disease Control and Prevention (U.S.); Clinical; Combined Modality Therapy; Cytoplasm; Dermacentor; Disease; Dose; Environment; Erythrocyte Membrane; Erythrocytes; Future; Genomics; Goals; Human; Immune response; Immunization; Immunobiology; Immunocompetent; Immunodominant Antigens; Immunoglobulin G; Immunoglobulin M; Incidence; Individual; Infection; Kinetics; Life Cycle Stages; Link; Malaria; Measures; Membrane; Molecular; Mus; Oregon; Orthologous Gene; Parasites; Pathogenesis; Pathologic; Pharmaceutical Preparations; Plasmodium falciparum; Predisposition; Protein Export Pathway; Protein Secretion; Proteins; Proteome; Proteomics; Recombinants; Reporting; Research; Serology; Spleen; Surface; System; Techniques; Ticks; United States; Vaccines; Virulence; Virulence Factors; Washington; associated symptom; base; detection assay; diagnostic assay; immunogenicity; in silico; macrophage; mouse model; nano; protective efficacy; response; side effect; success; tick-borne; transcriptomics; vaccine access; vaccine development; vaccine efficacy; vaccine trial

Human babesiosis is a tick-borne malaria-like illness with a worldwide distribution and endemic in the United States. The disease joined the list of CDC-nationally notifiable diseases in 2011 due to the increasing number of reported cases. The majority of clinical cases in the US have been linked to Babesia microti whereas Babesia duncani cases have been reported primarily from Washington, Oregon, and California. However, due to the lack of specific diagnostic assays and because immune competent individuals can be asymptomatic, the true incidence of babesiosis cases in the US and worldwide is most likely underestimated. There is no vaccine against human babesiosis and current therapies are not effective, require high doses and some of them are associated with major side effects. Even with these drugs and other supportive measures, the case fatality rate exceeds 20% in susceptible hosts. During the past 8 years, we gained significant understanding of the biology, pathogenesis and drug susceptibility of Babesia parasites that infect humans: (1) we completed the first genomic and transcriptomic analyses and annotations of B. microti and B. duncani; (2) probed the genomic diversity of B. microti in human blood and ticks; (3) demonstrated that B. microti and B. duncani are inherently tolerant to clinically recommended therapies; (4) discovered a combination therapy that results in radical cure of B. microti infection in mice; (5) completed the first immunoproteomic analysis of B. microti, identified the main immunodominant antigens of this parasite, and developed the first diagnostic assay for detection of active B. microti infection; and (6) discovered a vesicular-based secretion system used by the parasite to export some of its proteins to the host. Of particular relevance to the current RFA, we used immunoproteomic and proteomic approaches to identify secreted and surface-displayed proteins of B. microti and B. duncani, and for more than 30 B. microti antigens determine their serological profile in sera from infected mice and humans. The main hypothesis of this proposal is that some of the exported antigens of B. microti and B. duncani could serve as vaccines to illicit antibodies to block Babesia invasion of host erythrocytes or to facilitate elimination of Babesia- infected erythrocytes by host macrophages. The primary goals of this application are to further characterize the immunogenicity profile of these secreted antigens, and to conduct vaccination studies in mice to identify those antigens that could be developed as vaccines against Babesia microti and B. duncani infections. In Aim 1, we will produce functional recombinant forms of secreted and surface displayed proteins of B. microti and B. duncani and use them to determine the serological profile and kinetics of the humoral immune responses using mouse and human sera. In Aim 2. We will conduct cell biological studies to determine the secretion and cellular distribution of the candidate exported antigens during the intraerythrocytic life cycle of these parasites. In Aim 3, we will conduct immunization studies in mouse models of B. microti and B. duncani infections to identify those antigens that are effective vaccines when administered in human-compatible adjuvants.

人类巴贝斯虫病是一种蜱传的疟疾样疾病，在世界范围内分布，并在美国流行。 States. 2011年，由于越来越多的疾病， 报告的案件。美国的大多数临床病例与小巴氏杆菌有关， 报告的邓肯病例主要来自华盛顿、俄勒冈州和加州。但由于缺乏 特异性诊断测定的结果，并且由于免疫能力强的个体可能无症状， 在美国和世界范围内，巴贝虫病的发病率很可能被低估。目前还没有针对 人类巴贝斯虫病和目前疗法是无效的，需要高剂量，且其中一些与 有严重的副作用即使有这些药物和其他支持性措施，病死率仍超过 20%在敏感宿主中。在过去的8年里，我们对生物学有了很大的了解， 致病机制和药物敏感性的巴氏疟原虫感染人类：（1）我们完成了第一个基因组 以及B的转录组学分析和注释。microti和B.（2）探讨了B的基因组多样性。 （3）证明了B. microti和B.邓肯尼人天生就能容忍 临床推荐的治疗方法;（4）发现了一种根治B的联合治疗方法。田鼠 （5）完成了B的首次免疫蛋白质组学分析。microti，确定了主要的 免疫显性抗原，并开发了第一个诊断检测活性B。 microti感染;（6）发现了寄生虫使用的囊泡分泌系统，以输出一些 将其蛋白质输送到宿主体内。与当前RFA特别相关的是，我们使用了免疫蛋白质组学和蛋白质组学 鉴定B的分泌和表面展示蛋白的方法。microti和B.邓肯尼，超过 30 B B. Microti抗原决定了它们在感染小鼠和人血清中的血清学特征。主要 这一建议的假设是，某些输出的抗原是B。microti和B.邓肯尼可以担任 针对非法抗体的疫苗，以阻断巴氏杆菌侵入宿主红细胞或促进巴氏杆菌的消除， 被宿主巨噬细胞感染的红细胞本申请的主要目标是进一步表征 这些分泌的抗原的免疫原性谱，并在小鼠中进行疫苗接种研究，以确定这些 可以开发作为针对东方Bababelioti和B.邓肯尼感染目标1： 将产生分泌的和表面展示的B蛋白的功能性重组形式。microti和B.敦卡尼 并使用它们来确定使用小鼠的体液免疫应答的血清学特征和动力学， 和人血清。在目标2中。我们将进行细胞生物学研究，以确定分泌和细胞 在这些寄生虫的红细胞内生命周期期间候选输出抗原的分布。在目标3中， 我们将在B的小鼠模型中进行免疫研究。microti和B. Duncani感染，以确定那些 当在人相容的佐剂中施用时是有效疫苗的抗原。