Identification of Novel Efficacious Anti-Malarial Transmission Blocking Antigens Targeting the Female Gametocyte

鉴定针对雌性配子体的新型有效抗疟疾传播阻断抗原

• 批准号: MR/W025701/1
• 负责人: Andrew Blagborough
• 金额: $ 48.17万
• 依托单位: University of Cambridge
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FW025701%2F1
• 关键词: Identification; Novel; Efficacious; Anti; Malarial

Malaria remains a major global health challenge with an estimated 229 million new cases and 409,000 deaths in 2020. Appropriate use of currently existing anti-malarial healthcare tools have substantially reduced the global burden of disease, however, progress has recently stalled and morbidity and mortality remain unacceptably high, particularly in children under 5. It is widely accepted that new, innovative tools will be essential to achieve malaria control or elimination within the medium to long term. The causative agent of malaria, the protozoan parasite of the genus Plasmodium, is transmitted exclusively by Anopheles mosquitoes. Transmission of malaria through the mosquito is the weakest link in the chain that maintains the disease cycle; parasite numbers reach their lowest ebb during their developmental stages in the mosquito, and genetic variation is limited at these stages. This bottleneck represents a logical and proven point for interventions that kill the parasite at this point, creating a transmission-blocking effect. Examination, development and assessment of interventions specifically targeting malarial transmission is logical and timely. A potential manner of interrupting parasitic transmission directly is by targeting Plasmodium using transmission blocking vaccines (TBVs) against the parasitic sexual stages that mediate transmission to mosquitoes. Although a wide range of parasite proteins have been examined for TBV activity over the previous decades, there are still only five immunogens that unquestionably and reproducibly confer transmission blocking immunity. Surprisingly, discovery of these immunogens stems largely from historic studies, and to date, the majority of studies on gametocyte biology have (perhaps surprisingly) focused on male gametocytes. Very little is comparatively known about the surface of the female gametocytes. From our recent studies, utilising enhanced methods to exclusively isolate female gametocytes and examine their biology, we have shown that anti-malarial agents targeting female gametocytes can strongly inhibit parasitic transmission, demonstrating their viability as an anti-malarial target. Here, we propose to expand the range of available anti-female gametocyte TBV immunogens that result in potent transmission-blocking efficacy in the lab and field. We have identified 23 novel and previously examined female-TBV candidate targets, and will test their ability to block malarial transmission when administered as a vaccine in a rodent model. This model allows the effective triage of immunogenicity and efficacy of each candidate vaccine, within a cheap, scalable and ethical model, prior to translation to more costly, lower throughput, and more ethically challenging human malaria parasites. Only the best performing five of these potential vaccines will then be translated and examined using human malaria parasites, with resulting antibodies examined for their ability to directly block transmission of P. falciparum samples to mosquitoes within a malaria-endemic setting by Direct Membrane Feeding Assay. These results, obtained in a field, "human-only" assay, will facilitate future translation to direct human trials. Finally, in parallel, the levels of naturally occurring immune responses to these individual proteins will be assessed in protein samples from individuals in high and low transmission settings in Papua New Guinea, allowing us to understand the naturally occurring antibody responses to each of the 5 selected TBV antigens examined. We anticipate that the use of this novel approach to aid the design, assessment and use of a novel, potent anti-malarial TBV, could significantly contribute towards elimination and control efforts, while generating reagents to aid the potential expansion of our sparse knowledge of the process of plasmodial transmission in the future.

疟疾仍然是一个重大的全球健康挑战，估计2020年有2.29亿新病例和40.9万死亡病例。适当使用现有的抗疟疾保健工具已大大减少了全球疾病负担，但最近进展停滞，发病率和死亡率仍然高得令人无法接受，特别是在5岁以下儿童中。人们普遍认为，新的创新工具对于在中长期内实现疟疾控制或消灭至关重要。疟疾的病原体是疟原虫属的原生动物寄生虫，仅由按蚊传播。通过蚊子传播疟疾是维持疾病循环链中最薄弱的环节;寄生虫数量在蚊子体内发育阶段达到最低点，在这些阶段遗传变异有限。这个瓶颈代表了一个合乎逻辑的和经过验证的干预措施，在这一点上杀死寄生虫，创造一个传播阻断效应。审查、制定和评估专门针对疟疾传播的干预措施是合乎逻辑和及时的。直接阻断寄生虫传播的一种潜在方式是使用传播阻断疫苗（TBV）针对介导传播给蚊子的寄生虫性阶段。尽管在过去的几十年里，已经对广泛的寄生虫蛋白质进行了TBV活性的检查，但仍然只有五种免疫原毫无疑问地和可重复地赋予传播阻断免疫力。令人惊讶的是，这些免疫原的发现主要源于历史研究，迄今为止，大多数关于配子体生物学的研究（也许令人惊讶）集中在雄性配子体上。相对而言，对雌性配子体的表面知之甚少。从我们最近的研究中，利用增强的方法专门分离雌性配子体并检查它们的生物学，我们已经表明，靶向雌性配子体的抗疟疾药物可以强烈抑制寄生虫传播，证明它们作为抗疟疾靶标的可行性。在这里，我们建议扩大可用的抗雌性配子体TBV免疫原的范围，从而在实验室和现场产生有效的传播阻断效果。我们已经确定了23个新的和以前检查过的女性TBV候选目标，并将在啮齿动物模型中作为疫苗给药时测试其阻断疟疾传播的能力。该模型允许在转化为更昂贵、更低通量和更具伦理挑战性的人类疟疾寄生虫之前，在廉价、可扩展和伦理模型内对每种候选疫苗的免疫原性和功效进行有效的分类。然后，只有这些潜在疫苗中表现最好的五种疫苗将被翻译并使用人类疟疾寄生虫进行检查，通过直接膜饲养试验检查产生的抗体在疟疾流行环境中直接阻断恶性疟原虫样品传播给蚊子的能力。这些在“仅限人类”检测领域获得的结果将有助于未来转化为指导人体试验。最后，平行地，将在来自巴布亚新几内亚的高和低传播环境中的个体的蛋白质样品中评估对这些个体蛋白质的天然存在的免疫应答的水平，使我们能够理解对所检查的5种所选TBV抗原中的每一种的天然存在的抗体应答。我们预计，使用这种新的方法来帮助设计，评估和使用一种新的，有效的抗疟疾TBV，可以显着有助于消除和控制工作，同时产生试剂，以帮助我们的稀疏知识的疟原虫传播过程中的潜在扩展在未来。

项目成果

Effects of the G-quadruplex-binding drugs quarfloxin and CX-5461 on the malaria parasite Plasmodium falciparum.

• DOI: 10.1016/j.ijpddr.2023.11.007
• 发表时间: 2023-12
• 期刊: INTERNATIONAL JOURNAL FOR PARASITOLOGY-DRUGS AND DRUG RESISTANCE
• 影响因子: 4
• 作者: Craven, Holly M.;Nettesheim, Guilherme;Cicuta, Pietro;Blagborough, Andrew M.;Merrick, Catherine J.
• 通讯作者: Merrick, Catherine J.

Protein disulfide isomerases - a way to tackle malaria.

• DOI: 10.1016/j.pt.2023.05.007
• 发表时间: 2023-06
• 期刊: Trends in parasitology
• 影响因子: 9.6
• 作者: F. Angrisano;Amelia Ford;A. Blagborough;H. Bullen