Zoonotic Pathogen Growth Rate - A Marker for Disease Virulence and Therapy Resistance.

挑战：肝片形吸虫（或肝吸虫）是一种人畜共患病原体，可导致动物和人类的肝片形吸虫病。控制是不稳定的，在没有有效疫苗的情况下，依赖于一小批药物（杀吸虫剂），而抗药性正在增长。更有问题的是，只有一种杀吸虫剂对迁移的幼年吸虫有效，这种吸虫在通过肝脏的过程中引起急性疾病。我们有令人信服的证据表明，疾病的严重程度和药物敏感性受到病原体生长速度的深刻影响，但有关病原体生长的数据并不容易获得，因此不能用于指导对疾病暴发和强度的预测。需要从环境标志物的准确预测，以指导吸虫治疗方案。该项目旨在解决肝吸虫的这一不足，并确定新的生物标志物，以告知人畜共患寄生虫病风险的区域差异。动力计划：该项目建立在最近的发现和最先进的工具开发基础上，包括：（A）工具-体外培养，关闭基因以检查其功能的能力，了解吸虫行为和生物学的生物测定;（B）发现-确定癌症和肝吸虫干细胞共同的生长/发育途径，并控制病原体生长速率/存活。我们建议使用这些新的工具和资源，肝吸虫：探测改变的增长率对病原体生物学和药物敏感性的影响;使用“组学研究的幼年吸虫显示增强的增长，以确定生物标志物（或签名）增强的增长/毒力;和，使用这些新的生物标志物，以告知疾病风险的区域差异。过度假设：肝吸虫增强的疾病毒力和治疗抗性与快速生长和一组确定的生物标志物相关，这些生物标志物可用于识别疾病强度的区域差异和环境驱动因素，从而为基于实地的病原体控制提供信息。

The Challenge: Fasciola hepatica (or the liver fluke) is a zoonotic pathogen that causes the disease fasciolosis in animals and humans. Control is precarious and in the absence of an effective vaccine is reliant on a small portfolio of drugs (flukicides) to which resistance is growing. More problematic is the fact that only one flukicide is effective against the migrating juvenile fluke which causes acute disease during its passage through the liver. We have compelling evidence that disease severity and drug susceptibility are profoundly impacted by pathogen growth rate, but data on pathogen growth are not readily available and therefore are not used to guide forecasts on disease outbreaks and intensity. Accurate forecasts from environmental markers are needed to guide fluke treatment regimens. This project sets out to address this shortfall for liver fluke and identify new biomarkers to inform regional differences in zoonotic parasite disease risk. Project Impetus: The project is founded on recent discoveries and state-of-the-art tool developments, including: (A) Tools-in vitro culture, the ability to switch genes off to examine their function, bioassays to understand fluke behaviour and biology; (B) Discoveries-identification of growth/development pathways that are common to both cancer and liver fluke stem cells and which govern pathogen growth rate/survival. We propose to use these new tools and resources for liver fluke to: probe the impacts of altered growth rate on pathogen biology and drug susceptibility; to use 'omics studies of juvenile fluke displaying enhanced growth to identify biomarkers (or signatures) for enhanced growth/virulence; and, use these new biomarkers to inform regional differences in disease risk. Overarching hypothesis: Enhanced disease virulence and therapy resistance in liver fluke are associated with rapid growth and a defined panel of biomarkers that can be used to identify regional differences and environmental drivers of disease intensity, thereby informing field-based pathogen control.