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.

项目摘要 自2007年呼吁根除疟疾以来，研究和程序化的努力已转变为控制 疟疾通过鉴定和治疗临床疾病来消除感染和中断 疟疾传播。减少疟疾传播的努力包括杀死蚊子矢量的干预措施 和/或减少向量咬人或将人类减少到蚊子的传播，是性阶段的 通过治疗或传播阻断疫苗的疟原虫寄生虫。最近的研究描述了 寄生虫性承诺和配子细胞发展的分子机制。特别是 将AP2-G鉴定为Gametocytogenesis的主要调节剂，允许量化寄生虫性 基于AP2-G表达的估计值的承诺。大约是感染中寄生虫的1-30％ 表达AP2-G，表明并非感染中的所有无性寄生虫都承诺产生配子细胞。 但是，尚不完全了解导致寄生虫投资的因素。 几项研究已经确定了宿主，寄生虫和环境因素与环境因素之间的关联 配子细胞血症。需要更深入评估的潜在重要因素是多克隆的影响 关于寄生虫性投资。进化论表明，共同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差异的投资平衡； 但是，已经进行了有限的研究，以了解主宿内克隆的相互作用如何影响 恶性疟原虫感染中的配子细胞产生。因为高传播中很大一部分感染 区域是多克隆的，了解感染的复杂性如何影响性承诺和配子细胞血症 对于预测新干预措施对疟疾传播的影响很重要。同样，作为传输 （和感染的复杂性）响应干预措施的降低，了解 感染的复杂性和传播可能会在面对变化的情况下识别传输库 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 恶性疟原虫的性承诺和纵向同伴研究中发生的感染中的配子细胞血症 基于AP2-G基因以及男性和雌性配子细胞特异性基因的表达，在马拉维进行。 此外，我们将使用新开发的配子细胞基因分型标记来检查感染的复杂性 和克隆成分与给定克隆的配子细胞的相对频率和/或存在有关 在感染中。通过纵向研究的寄生虫在寄生虫中调查这些因素，我们希望 了解寄生虫生物学以及感染复杂性对寄生虫性投资的影响，以及 发现可行的关联，允许识别目标种群以减速传输 干预措施。