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

几乎每个生物体都必须应对病原体带来的有害感染。有机体可以通过杀死入侵的病原体(“抵抗力”)或减少病原体造成的损害(“耐受性”)来做出反应。在动物中，耐受性已经得到了很好的研究，但对耐受性的原因和后果知之甚少。这个项目关注的是20世纪90年代中期在后院常见的鸣禽--家雀身上出现的一种细菌疾病，它导致种群数量迅速下降。这种感染会导致严重的组织损伤，表现为结膜炎(红眼)。“耐受性”可能是减轻这种有害感染的重要方法。由于这种疾病在不同的时间传播到部分家雀范围，这项拟议的工作使用地理上分离的雀类种群之间的比较来揭示1)对一种新的病原体做出反应的“耐受性”演变得有多快，2)对耐受性起重要作用的基因表达机制，以及3)疾病在禽群中传播的“耐受性”的后果。该项目还设计了创新的方法，与公众交流其科学发现。研究人员加入了一个全球科学爱好者网络，建立了一个项目，每月举办一次公开活动，科学家或其他专家的简短演讲被音乐或艺术插曲隔开。多个活动将以此项目的结果为特色。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和最普遍的选择性力量之一。由于强有力的抵抗机制，如脊椎动物的炎性免疫反应，可能会破坏动物自身的组织，从而降低宿主的适应性，因此选择应该有利于不同宿主对感染的一定程度的耐受。然而，到目前为止，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，该项目直接提高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，以及宿主耐受性对病原体传播的影响。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，通过RNA-seq表达无数其他宿主基因)。此外，该项目使用实验性流行病将个体宿主反应的差异与病原体传播动态联系起来。通过这种比较技术、分子技术和实验技术的结合，这个项目整合了跨生物组织水平的耐受性的概念，将这种防御策略的原因和结果从分子连接到种群，所有这些都在一个自然发生的宿主-病原体系统中。最终，这项工作将显著提高对动物如何产生感染耐受性以及这种宿主反应如何影响病原体流行动态的知识。这一奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

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.