Impact of infection complexity on P. falciparum sexual commitment and gametocytemia

感染复杂性对恶性疟原虫性承诺和配子体血症的影响

• 批准号: 10681571
• 负责人: SHANNON Takala Harrison
• 金额: $ 23.18万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10681571
• 关键词: Adult; Age; Anopheles Genus; Antimalarials; Area; Biology; Bite; Blood; Bone Marrow; Child; Circulation; Clinical Treatment; Culicidae; DNA; DNA-Binding Proteins; Development; Disease; Dryness; Environmental Risk Factor; Epidemiology; Epigenetic Process; Equilibrium; Erythrocytes; Evaluation; Family; Female; Frequencies; Genes; Genetic; Genotype; Human; Immunity; Individual; Infection; Ingestion; Integration Host Factors; Interruption; Intervention; Invaded; Investments; Longitudinal cohort; Longitudinal cohort study; Malaria; Malawi; Midgut; Molecular; Parasites; Participant; Peripheral; Plasmodium; Plasmodium falciparum; Production; Proteins; Public Health; RNA; Research; Sampling; School-Age Population; Seasons; Sex Differentiation; Sexual Development; Sexual Reproduction; Stream; Symptoms; Target Populations; Vaccines; asexual; cohort; density; enhancer-binding protein AP-2; follow-up; heterochromatin-specific nonhistone chromosomal protein HP-1; insight; malaria transmission; male; public health relevance; response; theories; transmission blocking; transmission process; transmission-blocking vaccine; vector; vector mosquito

PROJECT SUMMARY Since the 2007 call for malaria eradication, research and programmatic efforts have shifted from controlling malaria through identification and treatment of clinical disease to elimination of infection and interruption of malaria transmission. Efforts to reduce malaria transmission include interventions to kill the mosquito vector and/or reduce vector biting or to reduce human to mosquito transmission of gametocytes, the sexual stage of the malaria parasite, through treatment or transmission-blocking vaccines. Recent studies have delineated the molecular mechanisms underlying parasite sexual commitment and gametocyte development. In particular, the identification of AP2-G as a master regulator of gametocytogenesis has allowed quantification of parasite sexual commitment based on estimates of ap2-g expression. Approximately, 1 – 30% of parasites in an infection express ap2-g, suggesting that not all asexual parasites in an infection commit to produce gametocytes. However, the factors that contribute to parasite investment in sexual reproduction are not fully understood. Several studies have identified associations between host, parasite, and environmental factors and gametocytemia. A potentially important factor that requires more in-depth evaluation is the impact of polyclonality on parasite sexual investment. Evolutionary theory suggests that competition of co-infecting parasite clones in a polyclonal infection can influence the balance in investment in asexual replication versus sexual differentiation; however, limited research has been performed to understand how within-host clone interactions impact gametocyte production in P. falciparum infections. Because a large proportion of infections in high transmission areas are polyclonal, understanding how infection complexity impacts sexual commitment and gametocytemia is important for predicting the impact of new interventions on malaria transmission. Likewise, as transmission (and infection complexity) decrease in response to interventions, understanding the relationship between infection complexity and transmission may allow identification of transmission reservoirs in the face of changing malaria epidemiology. In this study, we will examine the impact of host, parasite, and environmental factors on P. falciparum sexual commitment and gametocytemia in infections occurring in a longitudinal cohort study conducted in Malawi, based on expression of the ap2-g gene and male and female gametocyte-specific genes. In addition, we will use a newly developed gametocyte genotyping marker to examine how infection complexity and clone composition are associated with relative frequency and/or presence of gametocytes of a given clone within an infection. By investigating these factors in parasites from individuals followed longitudinally, we hope to gain insights into parasite biology and the impact of infection complexity on parasite sexual investment, and to discover actionable associations that allow identification of target populations for transmission-reducing interventions.

项目总结 自2007年呼吁根除疟疾以来，研究和方案努力已从控制 通过对疟疾临床疾病的识别和治疗来消除感染和阻断 疟疾传播。减少疟疾传播的努力包括消灭蚊子媒介的干预措施 和/或减少媒介叮咬或减少人对蚊子的配子体传播，性阶段 疟疾寄生虫，通过治疗或传播阻断疫苗。最近的研究已经描绘出 寄生虫性承诺和配子体发育的分子机制。尤其是， AP2-G被鉴定为配子细胞发生的主要调节因子使寄生虫的有性繁殖得以量化 基于ap2-g表达估计的承诺。大约1-30%的寄生虫在感染中 表达ap2-g，表明并不是所有感染中的无性寄生虫都承诺产生配子体。 然而，导致寄生虫有性繁殖投资的因素还没有完全被了解。 一些研究已经确定了宿主、寄生虫和环境因素之间的联系，以及 配子细胞症。需要更深入评估的一个潜在重要因素是多克隆的影响 寄生虫性投资。进化论认为，共感染寄生虫克隆的竞争 多克隆感染会影响无性复制与性别分化投资的平衡； 然而，为了了解主机内克隆交互如何影响，已经进行了有限的研究 恶性疟原虫感染过程中配子体的产生。因为很大比例的高传播性感染 这些领域是多克隆的，了解感染的复杂性如何影响性承诺和配子细胞症 对于预测新干预措施对疟疾传播的影响很重要。同样，作为变速器 (和感染复杂性)减少对干预措施的响应，了解两者之间的关系 感染的复杂性和传播可能允许在面临变化的情况下识别传输水库 疟疾流行病学。在这项研究中，我们将研究宿主、寄生虫和环境因素对 纵向队列研究中发生的感染中恶性疟原虫的性承诺和配子细胞症 在马拉维根据ap2-g基因和男女配子体特异基因的表达进行了研究。 此外，我们将使用一种新开发的配子体基因分型标记来检查感染的复杂性 和克隆组成与给定克隆的配子体的相对频率和/或存在相关联 在一次感染中。通过对纵向追踪的个体寄生虫中的这些因素进行研究，我们希望 深入了解寄生虫生物学和感染复杂性对寄生虫性投资的影响，以及 发现可行的关联，以便确定减少传播的目标人群 干预措施。