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

项目摘要 自2007年呼吁根除疟疾以来，研究和规划工作已从控制疟疾转向控制疟疾， 通过查明和治疗临床疾病，消除感染， 疟疾传播。减少疟疾传播的努力包括采取措施杀死蚊子媒介 和/或减少媒介叮咬或减少配子体的人到蚊子的传播， 疟疾寄生虫，通过治疗或传播阻断疫苗。最近的研究表明， 寄生虫性承诺和配子体发育的分子机制。特别是 鉴定出AP 2-G是配子体发生的主要调节因子， 基于AP 2-G表达的估计的承诺。大约1 - 30%的寄生虫感染 表达ap 2-g，表明并非所有感染的无性寄生虫都致力于产生配子体。 然而，导致寄生虫在有性生殖中投资的因素尚未完全了解。 一些研究已经确定了宿主、寄生虫和环境因素之间的联系， 配子体血症一个需要更深入评估的潜在重要因素是多克隆性的影响 寄生虫的性投资进化理论表明，在同一种寄生虫中， 多克隆感染可以影响无性复制与性分化投资的平衡; 然而，在了解宿主内克隆相互作用如何影响 恶性疟原虫感染中配子体的产生。因为在高传播率的感染中 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体血症 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 (and感染复杂性）对干预措施的反应减少，了解 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播储库。 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 P.一项纵向队列研究中发生的恶性疟原虫性承诺和配子体血症感染 在马拉维进行，基于ap 2-g基因和男性和女性配子体特异性基因的表达。 此外，我们将使用一种新开发的配子体基因分型标记来研究感染的复杂性， 和克隆组成与给定克隆的配子母细胞的相对频率和/或存在相关 在感染中。通过调查这些因素在寄生虫从个人纵向跟踪，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， 发现可采取行动的关联，以确定减少传播的目标人群 干预措施。

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.