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

感染的持续时间很重要，因为它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，感染持续时间是高度可变的--例如，宿主遗传、环境，甚至初始感染剂量的大小都可以决定感染是迅速清除还是变成慢性感染。这个项目将利用感染寄生虫的小鼠来调查感染持续时间不同的原因。研究人员将检验两个主要假设：感染持续时间由控制免疫细胞如何与寄生虫相互作用的反馈环控制；以及改变这些反馈强度的因素，如宿主遗传、环境和寄生虫的剂量，将可预见地改变感染持续时间。该项目将促进对控制急性和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化的方法。在此过程中，研究人员将培训下一代科学家，并通过与剧院的一项新合作，促进公众对免疫系统的理解。免疫系统和寄生虫之间的相互作用分享了许多优秀戏剧的特征：角色发展、关系和故事。这个项目将开发短剧和全规模的制作，向成千上万可能永远不会从事这一学科的观众教授基本免疫学。这项研究为感染持续时间的变化提出了一个新的生态学假说，即免疫反应中的正反馈机制产生“临界点”，驱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敏感，如感染剂量，宿主遗传或环境的变化可以通过加强清除或慢性化促进反馈机制来改变临界点的位置。研究人员将把机械数学模型与对小鼠品系的常规免疫学实验结合起来，这些品系的感染持续时间随着寄生虫剂量的增加而变化。实验将在实验室和室外完成，这样研究人员就可以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。这些方法将提供对自然人口中各种感染负担的原因的基本见解，并将导致检测生态系统中临界点行为的新方法。这项研究部分由一体化组织系统分部的共生、感染和免疫项目共同资助。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。

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.