F Ndungu, Pwani University, Determining Cellular Correlates of Immunity to Malaria in an Experimental Human Challenge Model of Exposed Adults

F Ndungu，普瓦尼大学，在暴露成人的实验人体挑战模型中确定疟疾免疫的细胞相关性

• 批准号: MR/P020321/1
• 负责人: Philip Bejon
• 金额: $ 96.75万
• 依托单位: University of Oxford
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2017
• 资助国家: 英国
• 起止时间: 2017 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FP020321%2F1
• 关键词: Ndungu; Pwani; University; Determining; Cellular

Malaria, caused by Plasmodium falciparum parasites, remains a major public health problem in sub-Saharan Africa, affecting over 50% of the population. However, the current control efforts are hampered by a multiplicity of challenges including persistent threats of emerging drug and insecticide resistant parasites and mosquitoes, respectively, and logistical challenges owing to insufficient funding and poor health infrastructure. The main hope for the complete control that will bring down malaria transmission dramatically to the point where elimination is a reality is effective vaccination. However, despite decades of work, the development of an effective antimalarial vaccine has been problematic. Ironically, the substantial investment in developing anti-malaria vaccines has not been matched with similar levels of investment in understanding either the mechanisms of immunity to malaria, or the reasons the limited success with test vaccines. Although, children living with endemic malaria acquire immunity that initially protects them from severe malaria and death, and then recurring episodes of mild disease, the mechanisms that control the severity of symptoms, production of protective antibody, and parasite growth in the immune individual remain major knowledge gaps. Much of what we know today about immunity to malaria comes from animal and human field studies, which are hard to translate directly to the mechanisms that control infection inside the human body. In contrast, deliberate experimental infections of humans with malaria would give more relevant and direct information on the human immune response to infection. Our preliminary data demonstrated variable blood stage parasite growth rates following experimental infections of Kenya adults, and these rates were inversely correlated with the baseline levels of the individual's immunity, indicating that parasite growth rates can be accurate measures of the level of naturally acquired immunity. We are now conducting a prospective screen to determine correlates of antibody-based immunity following experimental human infections of Kenyan adults with different levels of baseline immunity. Because the cellular responses that confers immunity and participates in the mechanisms that produce protective antibodies are not known, I am proposing to take advantage of this unique opportunity to test which cellular responses correlate with the ability of an individual to control infection (inflammation and parasite growth) following experimental malaria infections in Kenyan adults. My study will identify patterns of immune responses that can be used as predictive markers of an individual's ability to control inflammation, produce protective levels of high quality antibodies, and to control parasite growth.

由恶性疟原虫引起的疟疾仍然是撒哈拉以南非洲的一个主要公共卫生问题，影响着50%以上的人口。然而，目前的控制工作受到多种挑战的阻碍，包括新出现的对药物和杀虫剂有抵抗力的寄生虫和蚊子的持续威胁，以及由于资金不足和卫生基础设施差而带来的后勤挑战。彻底控制疟疾传播的主要希望是有效接种疫苗，这将使疟疾传播大幅下降到消除疟疾成为现实的地步。然而，尽管进行了几十年的工作，但有效的抗疟疾疫苗的开发一直存在问题。具有讽刺意味的是，在开发抗疟疾疫苗方面的大量投资，并没有与在了解疟疾免疫机制或测试疫苗有限成功的原因方面的投资水平相匹配。尽管患有地方性疟疾的儿童获得了最初保护他们免受严重疟疾和死亡以及随后反复发作的轻度疾病的免疫，但控制症状严重程度、保护性抗体的产生和免疫个体中寄生虫生长的机制仍然是主要的知识空白。我们今天所知道的对疟疾免疫的大部分来自动物和人类的实地研究，这些研究很难直接转化为控制人体内感染的机制。相比之下，故意实验性感染疟疾将为人类对感染的免疫反应提供更相关和直接的信息。我们的初步数据显示，在肯尼亚成年人实验感染后，不同血期的寄生虫增长率，这些增长率与个人免疫的基线水平呈负相关，表明寄生虫增长率可以准确地衡量自然获得性免疫水平。我们现在正在进行一项前瞻性筛查，以确定不同基线免疫水平的肯尼亚成年人受到实验性人类感染后基于抗体的免疫的相关性。由于赋予免疫力并参与产生保护性抗体的机制的细胞反应尚不清楚，我建议利用这个独特的机会来测试哪些细胞反应与个体在肯尼亚成年人实验性疟疾感染后控制感染(炎症和寄生虫生长)的能力相关。我的研究将确定免疫反应的模式，这些模式可以用作个人控制炎症、产生高质量抗体的保护性水平和控制寄生虫生长能力的预测标志。

项目成果

A framework for Controlled Human Infection Model (CHIM) studies in Malawi: Report of a Wellcome Trust workshop on CHIM in Low Income Countries held in Blantyre, Malawi.

• DOI: 10.12688/wellcomeopenres.12256.1
• 发表时间: 2017
• 期刊: Wellcome open research
• 作者: Gordon SB;Rylance J;Luck A;Jambo K;Ferreira DM;Manda-Taylor L;Bejon P;Ngwira B;Littler K;Seager Z;Gibani M;Gmeiner M;Roestenberg M;Mlombe Y;Wellcome Trust CHIM workshop participants
• 通讯作者: Wellcome Trust CHIM workshop participants

Proteomic analysis of extracellular vesicles from a Plasmodium falciparum Kenyan clinical isolate defines a core parasite secretome.

• DOI: 10.12688/wellcomeopenres.11910.2
• 发表时间: 2017
• 期刊: Wellcome open research
• 作者: Abdi A;Yu L;Goulding D;Rono MK;Bejon P;Choudhary J;Rayner J
• 通讯作者: Rayner J

Malaria exposure drives both cognate and bystander human B cells to adopt an atypical phenotype.

• DOI: 10.1002/eji.201948473
• 发表时间: 2020-08
• 期刊: European journal of immunology
• 影响因子: 5.4
• 作者: Aye R;Sutton HJ;Nduati EW;Kai O;Mwacharo J;Musyoki J;Otieno E;Wambua J;Bejon P;Cockburn IA;Ndungu FM
• 通讯作者: Ndungu FM

10-year longitudinal study of malaria in children: Insights into acquisition and maintenance of naturally acquired immunity.

• DOI: 10.12688/wellcomeopenres.16562.3
• 发表时间: 2021
• 期刊: Wellcome open research
• 作者: Addy JWG;Bediako Y;Ndungu FM;Valetta JJ;Reid AJ;Mwacharo J;Ngoi JM;Wambua J;Otieno E;Musyoki J;Said K;Berriman M;Marsh K;Bejon P;Recker M;Langhorne J
• 通讯作者: Langhorne J

Plasmodium falciparum adapts its investment into replication versus transmission according to the host environment.

• DOI: 10.7554/elife.85140
• 发表时间: 2023-03-14
• 期刊: eLife
• 影响因子: 7.7
• 作者: Abdi AI;Achcar F;Sollelis L;Silva-Filho JL;Mwikali K;Muthui M;Mwangi S;Kimingi HW;Orindi B;Andisi Kivisi C;Alkema M;Chandrasekar A;Bull PC;Bejon P;Modrzynska K;Bousema T;Marti M
• 通讯作者: Marti M