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

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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.