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

智力优势：在本提案中，Walker博士及其同事讨论了撒哈拉以南非洲（肯尼亚西部低地）全流行地区疟疾疾病系统的生态弹性和稳定性，该地区通过密集实施经杀虫剂处理的蚊帐（ITNs）来减少传播。研究活动由三个组成部分组成。首先，定量分析ITN实施对主要疟疾媒介冈比亚按蚊种群动态和种群遗传学的影响，重点关注种群平衡密度、与景观因子和传播强度的空间关系、种群遗传有效种群大小和基因流动。靶点杀虫剂抗性因子（所谓的击倒抗性或kdr）将作为基因流实证分析的标记。冈比亚按蚊与其姊妹种阿拉伯按蚊之比的大小被假定为ITN效应强度的有效量度。冈比亚按蚊种群假定不会因密度降低而补偿密度依赖性死亡率的降低。所谓的规模和潜在机制？社会效应?据推测，ITNs的减少与病媒从聚集分布到随机分布的变化以及死亡率导致的密度降低有关。进一步假设ITN的实施将加深该物种通常浅的种群结构，将限制基因流动，将种群数量减少到密度平衡以下的水平，增加arabiensis:gambiae比率的值，并将成年雌性分布从高度聚集转向相对于量化景观结构更加随机。其次，将利用微卫星标记和双氢叶酸抗生素耐药性和毒力（MSP-1）基因位点等位基因的频率，测量ITN实施对主要疟疾寄生虫恶性疟原虫种群遗传结构的影响。据推测，寄生虫种群结构将向高度克隆化方向发展，从而使具有耐药性和毒力的等位基因的基因流动受到限制。将从二倍体卵囊阶段的蚊子种群中取样寄生虫，以获得用于研究的克隆。通过检查与较高毒力相关的MSP-1等位基因的频率是否确实随着ITN的密集使用而增加，将检验传播率的降低为毒性更强的寄生虫菌株带来选择压力的广义假设。假定雄性配子体更受青睐，因为随着寄生虫密度的下降，寄生虫种群的有性繁殖受到限制。第三，将在社会科学的范围内，在与没有这种经验的人口相比，这些人口在使用国际间蚊帐方面有广泛的经验和知识的情况下，审查人口对国际间蚊帐的接受和利用模式。将审查ITN使用的空间格局是否符合基于传播强度空间变化的疟疾风险图。更广泛的影响：疾病作为生态系统，对系统扰动表现出很强的弹性和稳定性，特别是那些人为控制传播而强加给它们的扰动。人类疟疾是一个极好的例子，尽管它表面上简单，但一直抵制严格控制它的尝试，直到最近杀虫剂处理过的蚊帐成为一种强大而简单的控制工具。紧迫的问题是，这种疾病系统是否能够抵御这种扰动，这种弹性和稳定性的来源是什么？Walker博士的研究团队有着悠久的合作历史，并专注于肯尼亚西部低地疟疾媒介的生态和行为，自1998年以来，该地区一直在12.5万人口中实施针对疟疾传播的持续干预措施。该研究项目利用这一独特的机会来评估这种干预措施的长期效果，以及疟疾如何抵抗和克服它；或者如何使其可持续发展。该项目涉及密歇根州立大学的一名研究生，他将在肯尼亚与不同的工作人员一起工作。

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.