Collaborative Research: Ecology of expulsion: within-host dynamics driving nematode infection

合作研究：驱逐生态学：驱动线虫感染的宿主内动态

• 批准号: 2153923
• 负责人: Andrea Graham
• 金额: $ 67.14万
• 依托单位: Princeton University
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-15 至 2025-07-31
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2153923&HistoricalAwards=false
• 关键词: Collaborative; Research; Ecology; expulsion; within

The duration of an infection is important because it affects how long a host is sick, and thus how long the host can transmit the infection to others. However, infection duration is highly variable – for example, host genetics, environment, and even the size of the initial infectious dose can determine if an infection is cleared quickly or becomes chronic. This project will investigate the causes of varied infection duration using mice infected with parasitic worms. The researchers will test two main hypotheses: that infection duration is governed by feedback loops that control how immune cells interact with the parasite and with one another; and that factors that change the strength of those feedbacks, like host genetics, environment, and dose of parasites, will predictably change infection duration. This project will advance understanding of the immunological processes that govern acute versus chronic worm infections and will establish methods for understanding chronicity of other type of infections. Along the way, the researchers will train the next generation of scientists and advance public understanding of immune systems through a novel collaboration with theater. The interaction between the immune system and parasites shares many of the features of good drama: character development, relationships, and story. This project will develop short plays and full-scale productions that teach basic immunology to thousands of audience members who might never be otherwise engaged in the subject.This research proposes a novel ecological hypothesis for variation in infection duration, namely that positive feedback mechanisms within the immune response generate “tipping points” that drive the system towards either chronic infection or rapid clearance. These tipping points make interactions between the immune system and parasites sensitive to initial conditions, such as infectious dose, and variation in host genetics or the environment can alter the location of tipping points by strengthening clearance- or chronicity-promoting feedback mechanisms. The researchers will combine mechanistic mathematical models with conventional immunological experiments on mouse strains that vary in how infection duration changes with increasing doses of a parasitic helminth. Experiments will be completed both in the lab and outdoors, so that the researchers can explore how a natural environment influences the strength of immunological feedbacks and thus infection duration. These approaches will provide fundamental insights into the causes of varied burden of infection in natural populations and will lead to novel ways of detecting tipping point behavior in ecological systems. This research is co-funded in part by the Symbioses, Infection, and Immunity Program in the Division of Integrative Organismal Systems.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.

感染的持续时间很重要，因为它会影响宿主患病的时间，从而影响宿主将感染传播给其他人的时间。然而，感染持续时间变化很大——例如，宿主遗传学、环境，甚至初始感染剂量的大小都可以决定感染是很快被清除还是变成慢性。该项目将利用感染寄生虫的小鼠来调查不同感染持续时间的原因。研究人员将测试两个主要假设：感染持续时间由反馈回路控制，反馈回路控制免疫细胞与寄生虫以及彼此之间的相互作用；改变这些反馈强度的因素，如宿主遗传学、环境和寄生虫剂量，将可预见地改变感染持续时间。该项目将增进对控制急性与慢性蠕虫感染的免疫过程的了解，并将建立了解其他类型感染的慢性病的方法。在此过程中，研究人员将通过与剧院的新颖合作来培训下一代科学家并增进公众对免疫系统的了解。免疫系统和寄生虫之间的相互作用具有许多优秀戏剧的特征：角色发展、关系和故事。该项目将开发短剧和大型作品，向数千名可能永远不会参与该主题的观众教授基础免疫学。这项研究针对感染持续时间的变化提出了一种新的生态假设，即免疫反应中的正反馈机制会产生“临界点”，推动系统走向慢性感染或快速清除。这些临界点使免疫系统和寄生虫之间的相互作用对初始条件（例如感染剂量）敏感，而宿主遗传学或环境的变化可以通过加强清除或慢性促进反馈机制来改变临界点的位置。研究人员将机械数学模型与传统的小鼠品系免疫学实验相结合，这些小鼠品系的感染持续时间随着寄生蠕虫剂量的增加而变化。实验将在实验室和室外完成，以便研究人员能够探索自然环境如何影响免疫反馈的强度，从而影响感染持续时间。这些方法将为自然群体中不同感染负担的原因提供基本见解，并将带来检测生态系统临界点行为的新方法。这项研究由综合有机系统部门的共生、感染和免疫计划共同资助。该奖项反映了 NSF 的法定使命，并通过使用基金会的智力价值和更广泛的影响审查标准进行评估，被认为值得支持。