Emerging zoonotic malaria in Malaysia: strengthening surveillance and evaluating population genetic structure to improve regional risk prediction tools

项目总结/摘要 东南亚仍然是新发人畜共患传染病的全球热点。近期 猴疟疾寄生虫诺氏疟原虫的传播增加， 东南亚，证实了土地使用的变化如何导致疾病蔓延到人类。在 在马来西亚，诺氏疟原虫现在占疟疾病例的绝大多数， 疟疾相关死亡的主要原因。最近的报告表明，P. knowlesi也是 印度尼西亚西部部分地区的主要物种，由于显微镜的错误鉴定， 诊断不足的情况可能在整个区域普遍存在。分子监测对于 监测人畜共患诺氏疟原虫的出现，为疟疾控制战略提供信息， 评估消灭人类独有的疟疾种类的进展情况。 在马来西亚沙巴的这项研究中，我们首先计划进一步改进分子状态的疟疾 监测检测系统，以监测不断变化的流行病学和临床特征， 疾病，包括在怀孕期间，这可能会发生与适应P.诺氏 人传人我们将补充这些数据与有针对性的纵向健康 对健康和发热的参加者进行设施调查，以了解无症状或 亚显微诺氏疟原虫感染，除了筛查其他猿类疟疾物种外， 例如食蟹猴疫霉。一个高通量多重血清学疟疾监测平台将 也可用于整合最近开发的靶向诺氏疟原虫的新抗原。这个平台 将能够评价诺氏疟原虫暴露和传播的群体水平标志物 在对其他人类疟疾的跨物种免疫力可能减弱的情况下， 物种，并允许同时评估其他公共卫生优先事项，包括SARS-CoV-2。 其次，微单体型的多重深度靶向测序的最新进展提供了 潜在的优势，如果这些工具适用于P. knowlesi。我们之前的监测研究 收集了超过5500个诺氏疟原虫分离株，我们计划开发新的基于基因组的工具来评估 P. knowlesi种群结构，以足够的分辨率了解不断增加的传播， 疾病的严重程度在沙巴，并与这些发现在东南亚其他地方。最后我们将 还使用一个更新的地理参考数据库的全州P.诺氏病例随着时间的推移， 改变精细的空间尺度发病模式，并产生区域预测P。 knowlesi风险图，纳入环境遥感卫星数据， 人类、猴子和蚊子种群分布情况，为规划、监测 以及在该区域有诺氏疟原虫传播风险的其他国家开展预防活动。

Project Summary/Abstract Southeast Asia remains a global hotspot for emerging zoonotic infectious diseases. The recent increase in transmission of the monkey malaria parasite Plasmodium knowlesi, endemic to Southeast Asia, exemplifies how land-use change can drive disease spill-over to humans. In Malaysia, P. knowlesi now accounts for the vast majority of malaria cases and is the predominant cause of malaria-related deaths. Recent reports suggest that P. knowlesi is also the predominant species in parts of western Indonesia, and that due to misidentification by microscopy, under-diagnosis is likely widespread across the region. Molecular surveillance is essential for monitoring the emergence of zoonotic P. knowlesi, informing malaria control strategies, and assessing progress towards elimination of the human-only malaria species. In this study in Sabah, Malaysia, we firstly plan to further improve molecular state-wide malaria surveillance detection systems to monitor for changing epidemiological and clinical features of disease, including in pregnancy, which potentially could occur with adaption of P. knowlesi to human-human transmission. We will supplement these data with targeted longitudinal health facility surveys of healthy and febrile attendees to understand the true burden of asymptomatic or submicroscopic P. knowlesi infections, in addition to screening for other simian malaria species such as P. cynomolgi. A high-throughput multiplex serological malaria surveillance platform will also be used to integrate recently developed novel antigens targeting P. knowlesi. This platform will enable evaluation of population-level markers of P. knowlesi exposure and transmission intensity in the context of potential waning cross-species immunity from other human malaria species, and allow concurrent assessment of other public health priorities including SARS-CoV-2. Secondly, recent advances in multiplexed deep targeted sequencing of microhaplotypes offer potential advantages if these tools are adapted for P. knowlesi. Our previous surveillance study collected >5500 P. knowlesi isolates, and we plan to develop novel genome-based tools to evaluate P. knowlesi population structure at sufficient resolution to understand increasing transmission and disease severity in Sabah, and relate these findings to elsewhere in Southeast Asia. Finally, we will also use an updated georeferenced database of state-wide P. knowlesi cases over time to characterise changing fine spatial scale incidence patterns, and to generate regional predictive P. knowlesi risk mapping incorporating environmental remote-sensing satellite data and predicted human, monkey and mosquito population distributions to inform and guide planning, surveillance and prevention activities in other countries in the region at risk of P. knowlesi transmission.