Collaborative Research: Immune mechanisms and epidemiological consequences of tolerance in a naturally occurring host-pathogen system

合作研究：自然发生的宿主-病原体系统中耐受性的免疫机制和流行病学后果

• 批准号: 1754872
• 负责人: Dana Hawley
• 金额: $ 30.87万
• 依托单位: Virginia Polytechnic Institute and State University
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-05-15 至 2024-04-30
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1754872&HistoricalAwards=false
• 关键词: Collaborative; Research; Immune; mechanisms; epidemiological

Nearly every organism has to cope with harmful infections from pathogens. Organisms can respond by either killing invading pathogens ('resistance') or by reducing the damage caused by pathogens ('tolerance'). Among animals, resistance has been well studied, but relatively little is known about the causes and consequences of tolerance. This project focuses on a bacterial disease that emerged in the mid-1990s in a common backyard songbird, the house finch, causing rapid population declines. This infection causes severe tissue damage, in the form of conjunctivitis (pink-eye). 'Tolerance' is likely an important way to mitigate this harmful infection. Because the disease reached parts of the house finch range at distinct times, the proposed work uses comparisons among geographically separated finch populations to uncover 1) how quickly 'tolerance' evolves in response to a novel pathogen, 2) the gene expression mechanisms important for tolerance, and 3) the consequences of 'tolerance' for disease spread within flocks. This project also crafts innovative means to communicate its scientific findings with the public. The researchers have joined a global network of science enthusiasts by founding a program that hosts monthly public events where short presentations by scientists or other experts are separated by musical or artistic interludes. Multiple events will feature results from this project. In addition, through a graduate-level course at Virginia Tech this project will train young scientists and educators to design their own programs that enhance public engagement with science.Infectious diseases are among the most powerful and pervasive selective forces on the planet. Because vigorous resistance mechanisms, such as inflammatory immune responses in vertebrates, can reduce host fitness by damaging an animal's own tissues, selection should favor some degree of tolerance of infection across diverse hosts. To date, however, work on animals has focused almost exclusively on resistance. By combining molecular techniques and inter-population comparisons, this project directly advances our knowledge of three of the most critical, open issues in the study of animal tolerance: how selection shapes this host strategy following disease emergence, the immune mechanisms underlying tolerance, and the consequences of host tolerance for pathogen transmission. The work utilizes a number of techniques to assess immune responses rarely tested in non-model organisms (e.g., expression of songbird cytokine genes through qPCR and expression of myriad other host genes through RNA-seq). In addition, this project uses experimental epidemics to link differences in individual host responses with pathogen transmission dynamics. Through this combination of comparative, molecular, and experimental techniques, this project integrates the concept of tolerance across levels of biological organization, linking the causes and consequences of this defense strategy from molecules to populations, all in a naturally occurring host-pathogen system. Ultimately, this work will significantly advance knowledge of how tolerance of infection arises in animals and how this host response impacts the dynamics of pathogen epidemics.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

几乎每一种生物体都必须应对来自病原体的有害感染。生物体的反应要么是杀死入侵的病原体（“抗性”），要么是减少病原体造成的损害（“耐受性”）。在动物中，耐药性已经得到了很好的研究，但对耐受性的原因和后果却知之甚少。这个项目的重点是20世纪90年代中期出现在一种常见的后院鸣鸟——家雀身上的一种细菌疾病，这种疾病导致了种群数量的迅速下降。这种感染导致严重的组织损伤，以结膜炎（红眼）的形式出现。“耐受性”可能是减轻这种有害感染的重要途径。由于疾病在不同的时间到达部分家雀范围，因此拟议的工作使用地理上分离的雀群之间的比较来揭示1)对新病原体的“耐受性”进化速度有多快，2)对耐受性重要的基因表达机制，以及3)“耐受性”对疾病在群内传播的后果。该项目还以创新的方式与公众交流其科学发现。这些研究人员加入了一个由科学爱好者组成的全球网络，他们创建了一个项目，每月举办一次公开活动，在这个活动中，科学家或其他专家的简短演讲被音乐或艺术插曲隔开。多个事件将以该项目的结果为特色。此外，通过弗吉尼亚理工大学的研究生课程，该项目将培训年轻的科学家和教育工作者设计他们自己的项目，以加强公众对科学的参与。传染病是地球上最强大、最普遍的选择性力量之一。因为强大的抵抗机制，如脊椎动物的炎症免疫反应，可以通过破坏动物自身组织来降低宿主的适应性，所以选择应该在一定程度上支持不同宿主对感染的耐受。然而，迄今为止，对动物的研究几乎完全集中在耐药性上。通过结合分子技术和种群间比较，该项目直接推进了我们对动物耐受性研究中三个最关键、最开放的问题的认识：疾病出现后，选择如何塑造宿主策略，耐受性背后的免疫机制，以及宿主对病原体传播的耐受性的后果。这项工作利用了许多技术来评估在非模式生物中很少测试的免疫反应（例如，通过qPCR表达鸣禽细胞因子基因和通过RNA-seq表达无数其他宿主基因）。此外，本项目利用实验流行病将个体宿主反应的差异与病原体传播动力学联系起来。通过比较、分子和实验技术的结合，该项目整合了跨生物组织水平的耐受性概念，将这种防御策略从分子到种群的原因和后果联系起来，所有这些都在自然发生的宿主-病原体系统中。最终，这项工作将显著推进对感染耐受如何在动物中产生以及这种宿主反应如何影响病原体流行动力学的认识。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。