Reducing Parasite Transmission Across a Varied Lanscape: Ecological and Social Contexts of a Malaria Intervention

学术价值：在这项提案中，Walker博士和他的同事解决了撒哈拉以南非洲(低地，肯尼亚西部)全流行地区疟疾疾病系统的生态复原力和稳定性问题，即通过密集实施经杀虫剂处理的蚊帐(ITN)来故意操纵疟疾系统，以减少传播。研究活动由3个综合组成部分组成。首先，将量化实施ITN对主要疟疾媒介冈比亚按蚊的种群动态和种群遗传学的影响，重点关注种群平衡密度、与景观因素和传播强度的空间关系、种群遗传有效种群规模和基因流动。靶点杀虫剂抗性因子(所谓的击倒抗性或kdr)将被用作基因流动的经验分析的标志。冈比亚按蚊与其姊妹物种阿拉伯按蚊的比率大小被认为是ITN效应强度的有效衡量标准。冈比亚按蚊种群被认为不会对密度减少做出反应，而是补偿密度依赖死亡率的减少。所谓的社区效应的大小和潜在的机制是什么？据推测，ITN的变化与病媒从聚集分布到随机分布的变化以及由于死亡率导致的密度降低有关。ITN的实施将进一步深化该物种通常较浅的种群结构，将限制基因流动，将种群减少到低于密度平衡的水平，增加阿拉伯与冈比亚的比率，并将相对于量化的景观结构将成年雌性分布从高度聚集转变为更随机。其次，将利用微卫星标记的组合来测量ITN实施对恶性疟原虫种群遗传结构的影响，以及操作在二氢叶酸抗生素耐药性和毒力(MSP-1)基因座上的等位基因频率。假设寄生虫种群结构将深化为高度克隆的结构，从而导致与毒力相关的抗药性等位基因的基因流动受到限制。在二倍体卵囊阶段，将从蚊子种群中提取寄生虫样本，以获得克隆供研究。传播率的降低会给毒力更强的寄生虫菌株带来选择压力，这一普遍假设将通过检验MSP-1上那些与毒力更高相关的等位基因是否真的随着ITN的大量使用而增加频率来检验。随着寄生虫密度的下降，由于寄生虫种群的有性繁殖受到限制，雄配子细胞被认为是受青睐的。第三，将在社会科学的背景下，与没有这种经验的人口相比，在对使用ITN有广泛经验和知识的情况下，审查该人口对ITN的接受度和利用模式。将审查ITN使用的空间模式是否符合基于传播强度空间变化的疟疾风险图。广泛影响：疾病作为生态系统对系统扰动表现出很强的复原力和稳定性，特别是人类强加给它们的那些故意试图控制传播的扰动。人类疟疾是一个最好的例子，尽管它表面上很简单，但它一直抵制严格的控制努力，直到最近，杀虫剂处理的蚊帐已经成为一种强大而简单的控制工具。迫在眉睫的问题是，这个疾病系统能否抵御这种干扰，这种韧性和稳定性的来源是什么？沃克·S的研究团队在肯尼亚西部低地的疟疾媒介生态和行为方面有着很强的合作和专注努力的历史，自1998年以来，那里的12.5万人口一直在实施持续的干预措施，以遏制疟疾的传播。该研究计划利用这一独特的机会来评估这种干预措施的长期效果，以及疟疾可能如何抵抗和克服它，或者如何使其可持续。该项目涉及密歇根州立大学的一名研究生，他将与肯尼亚的不同工作人员一起工作。

Intellectual merit: In this proposal, Dr. Walker and colleagues address ecological resiliency and stability of the malaria disease system in a holoendemic area of sub-Saharan Africa (lowland, western Kenya) when it is manipulated intentionally by intensive implementation of insecticide treated bed nets (ITNs) to reduce transmission. Research activities consist of 3 integrated components. First, the effects of ITN implementation on the population dynamics and population genetics of the main malaria vector, Anopheles gambiae will be quantitated, with attention to population equilibrium density, spatial relationships to landscape factors and transmission intensity, population genetic effective population size, and gene flow. Target site insecticide resistance factors (so-called knockdown resistance or kdr) will be used as a marker for empirical analysis of gene flow. The magnitude of the ratio of Anopheles gambiae to its sister species Anopheles arabiensis is postulated to be a valid measure of the intensity of the ITN effect. Anopheles gambiae populations are postulated not to respond to density reductions with compensating reductions in density-dependent mortality. The magnitude and underlying mechanism of the so-called ?community effect? of ITNs is postulated to be related to a change from aggregated to random distribution of vectors combined with a reduced density owing to mortality. ITN implementation is further postulated to deepen the normally shallow population structure of this species, will restrict gene flow, will reduce populations to levels below density equilibrium, increase the value of the arabiensis:gambiae ratio, and will shift adult female distribution from highly aggregated to more random relative to quantified landscape structure. Secondly, the effects of ITN implementation on population genetic structure of the primary malaria parasite, Plasmodium falciparum will be measured, using a combination of microsatellite markers, and frequencies of alleles operating at dihydrofolate antibiotic resistance and virulence (MSP-1) gene loci. It is hypothesized that a parasite population structure will deepen into a highly clonal one, such that gene flow of alleles conferring drug resistance and related to virulence will be restricted. Parasites will be sampled from the mosquito population at the diploid oocyst stage, to obtain clones for study. The generalized hypothesis that reduction in transmission rate confers selection pressure for more virulent parasite strains will be tested by examining whether those alleles at MSP-1 associated with higher virulence indeed increase in frequency with intensive ITN use. Male gametocytes are postulated to be favored, owing to limits on parasite population sexual reproduction as densities of parasites decline. Thirdly, the acceptability and utilization patterns by the human population of ITNs will be examined in the social science context under conditions where that population has extensive experience and knowledge of ITN use, compared to human populations that do not have this experience. Whether spatial patterns of ITN use conform to risk maps of malaria based upon spatial variations in transmission intensity will be examined.Broader impacts: Diseases as ecological systems show strong resiliency and stability to system perturbations, in particular those imposed on them by humans as an intentional attempt to control transmission. Human malaria represents a supreme example, where despite its apparent simplicity it has resisted rigorous attempts to control it, until very recently when insecticide treated bed nets (ITNs) have emerged as a powerful and simple control tool. The pressing question is, will this disease system resiliently resist this perturbation, and what are the sources of the resiliency and stability?Dr. Walker''s research team has a strong history of collaboration and of focused efforts on ecology and behavior of malaria vectors in lowland, western Kenya, where an on-going intervention against malaria transmission has been imposed since 1998 in a human population of 125,000. The research program takes advantage of this unique opportunity to evaluate the long term efficacy of this intervention and how malaria might resist and overcome it; or how it might be made sustainable. The project involves a graduate student from Michigan State University who will work with a diverse staff in Kenya.