Temporal strain structure and response to interventions in a high endemicity region of Plasmodium falciparum

恶性疟原虫高流行区的时间应变结构和对干预措施的反应

基本信息

批准号：
10656444
负责人：
Karen Patricia Day
金额：
--
依托单位：
UNIVERSITY OF CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-07-19 至 2023-09-01
项目状态：
已结题

项目摘要

Malaria control and elimination in areas of high transmission in sub-Saharan Africa present a significant challenge to global health. A large fraction of the population across all ages in these areas harbor Plasmodium falciparum without clinical manifestations, providing a vast reservoir of infection for transmission. This asymptomatic reservoir is sustained by the enormous antigenic diversity of the parasite. Thus, the challenge for hyperendemic regions requires that the malaria field comes to terms with such diversity, studying it as a complex adaptive system. This study addresses the two-way interaction between epidemiology and P. falciparum diversity from the perspective of the multigene and highly recombinant family known as var, which encodes for the major antigen of the blood stage of infection. This project combines theory with field and laboratory work lo generate new understanding of the diverse transmission reservoir of P. falciparum and its resilience to elimination. The first aim is the longitudinal deep sampling of this reservoir in the Bongo District, Ghana following two control interventions (i.e. indoor residual spraying and seasonal malaria chemoprevention). On the basis of age-stratified serial cross-sectional data, this study will assess how informative the var system is to monitor this reservoir under conditions of the control interventions, compared to traditional malariometric indices and neutral molecular markers. The second aim develops strain theory based on a stochastic agent-based model that tracks the history of infection of each host and the evolutionary change of the parasite. Pathogen population structure over time and responses of the var system to intervention are investigated in ways that inform both molecular data analyses and control efforts. The third aim develops a transmission model of intermediate complexity that can be fitted to routine epidemiological data but still incorporates the major effects of parasite diversity on epidemiology. In particular, the existence of a threshold in transmission intensity that impacts parasite antigenic diversity will be investigated. Contributions include computational models at the interface of epidemiology and evolution, and network analyses of population genetic structure applicable to other multigene families of P. falciparum, as well as to other pathogens whose immune escape relies on highly-recombinant gene families.

撒哈拉以南非洲地区高传播领域的疟疾控制和消除对全球健康构成了重大挑战。在这些地区，所有年龄段的人口中有很大一部分在没有临床表现的恶性疟原虫中，为传播提供了广泛的感染水库。这种无症状的储层是由寄生虫的巨大抗原多样性所维持的。因此，对高流行区域的挑战要求疟疾领域与这种多样性相关，将其研究为一个复杂的自适应系统。从多基因和高度重组家族的VAR的角度来看，这项研究探讨了流行病学与恶性疟原虫多样性之间的双向相互作用，该家族被称为VAR，该家族编码感染的血液阶段的主要抗原。该项目将理论与实验室和实验室工作相结合，从而产生了对恶性疟原虫的多样传播储藏及其对消除的韧性的新了解。第一个目的是在两种控制干预措施（即室内残留喷涂和季节性疟疾化学措施）之后，在加纳邦戈区进行了该水库的纵向深度采样。根据年龄分层的串行横截面数据，本研究将评估VAR系统在控制干预措施条件下监测该储层的信息，与传统的疟疾测量指数和中性分子标记相比。第二个目的是基于基于随机剂的模型来发展应变理论，该模型跟踪每个宿主的感染历史和寄生虫的进化变化。随着时间的流逝，病原体种群的结构以及VAR系统对干预的反应，以依据分子数据分析和控制工作的方式进行研究。第三个目标开发了一个中间复杂性的传输模型，该模型可以适合常规流行病学数据，但仍包含寄生虫多样性对流行病学的主要影响。特别是，将研究影响寄生虫抗原多样性的传播强度的阈值。贡献包括在流行病学和进化的界面上的计算模型，以及适用于恶性疟原虫的其他多基因家族的种群遗传结构的网络分析，以及其他病原体的免疫逃脱依赖于高度兼容基因家族的病原体。