The investigators will examine, at the molecular level in a worm model, how the nervous system regulates immune responses to infections to prevent either insufficient or excessive immune activation.
The body’s innate immune system, its first line of defense, recognizes infectious microorganisms such as bacteria, and initiates a generalized short-acting response while summoning the body’s adaptive immune cells to mount a sustained and targeted attack. Insufficient innate immune responses can allow cancers to grow unchallenged or enable infections to spread. Overzealous immune responses, meanwhile, can lead to massive inflammation or to “autoimmune” diseases in which immune cells mistakenly attack the body’s own tissues. Why study the roundworm to understand how the nervous system controls innate immunity in humans? The roundworm has only 302 neurons and these and the worm’s genetics are becoming well characterized; some key features of innate immunity evolutionarily appear to be shared by worms and humans; and, both the worm and human intestine prevent harmful microbes from colonizing through similar methods. Apparently the worm’s nervous system receives signals from infected cells and integrates them to coordinate an appropriate immune response, while the immune system may recognize microbes and their toxins that otherwise go undetected. Yet bacteria are capable of inhibiting the roundworm’s innate immune system and killing the worm using different processes. Understanding successful and unsuccessful neural-immune interactions in controlling infections in the worm, therefore, may provide important insights for protecting against human infectious disease.
The investigators’ prior worm research found that a receptor, called NPR-1, is located on nervous system cells and participates in a neural network that controls innate immunity in the worm. They hypothesize that these “G-protein coupled receptors” function either by directly recognizing harmful bacteria, or by receiving signals from infected cells and facilitating a coordinated immune response through bi-directional signaling between neural and immune cells. To study this they will identify: 1) neurons that have the G-protein coupled receptor; 2) the neural circuit they comprise and study the flow of signaling between neurons in this network; and, 3) the signals involved in neuron to neuron, and neuron to immune cell communication. The findings are anticipated to provide new targets for therapeutic interventions against human infections.
Significance: Understanding how the nervous system controls immune responses to bacterial infection in the worm may lead to new targets for therapeutic interventions in humans to protect against or more effectively treat infectious diseases, while limiting excessive immune responses that may produce autoimmune disease.