Role of the Nervous System in Response to Pathogen Infection

Alejandro Aballay, Ph.D.

Funded in September, 2009: $200000 for 3 years
LAY SUMMARY . ABSTRACT . BIOGRAPHY .

LAY SUMMARY

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Learning how the nervous system regulates immune responses to infections

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.   

ABSTRACT

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Innate immunity comprises a variety of mechanisms used by metazoans to prevent microbial infections. Activation of the innate immune system upon pathogen recognition results in a rapid and definitive microbicidal response to invading microorganisms that is fine-tuned to prevent deleterious deficiencies or excesses in the response. While insufficient immune responses can lead to infection and cancer, excessive immune responses have been linked to conditions such as Crohn’s disease, rheumatoid arthritis, atherosclerosis, diabetes, and Alzheimer’s disease. Thus, a detailed understanding at the molecular level of how the nervous system may regulate the immune system is of major relevance for human health. The nervous system, which can recognize microorganisms and microbial toxins, has several characteristics that make it an ideal partner with the innate immune system to regulate host defenses. However, even though a large body of evidence indicates that metazoan innate immunity is under the control of the nervous system, the mechanisms involved in the process remain unclear. To provide insights into the neural mechanisms involved in the recognition of pathogens and regulation of innate immunity, we have taken advantage of the simple and well studied nervous and immune systems of the nematode Caenorhabditis elegans. Our studies show that specific genes and neurons in the nervous system of C. elegans control immune responses, indicating that cell non-autonomous signals from different neurons may act on non-neural tissues to regulate innate immunity. Additional studies suggest that neurons located in sensory organs that are infected by bacterial pathogens may use GPCRs to activate immune responses at the cellular and organismal levels. Thus, we propose to explore the general hypothesis that GPCRs participate in neural circuits that either recognize bacterial pathogens directly or receive inputs from non-neuronal infected cells and integrate them to coordinate appropriate immune responses. Given the conserved nature of GPCR-mediated signaling and of innate immune responses, the proposed studies should lead to a better understanding of the mechanisms by which the human nervous system may respond to bacterial infections by activating innate immune pathways in neural cells and by potentially coordinating organismal responses.

INVESTIGATOR BIOGRAPHIES

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Alejandro Aballay, Ph.D.

Dr. Alejandro Aballay is an Associate Professor at the Department of Molecular Genetics and Microbiology, Duke University Medical School. In 1998, he earned his Ph.D. at Nacional de Cuyo University in Argentina and received a Pew Fellowship to move to St. Louis, where he continued his studies in endocytosis at Washington University. In 1999, following an interest in bacterial pathogenesis he developed while studying the intracellular transport of Brucella abortus when he was a graduate student, he moved to Boston to join the Ausubel laboratory at Harvard Medical School. Dr. Aballay moved to Durham in 2002 to join the Department of Molecular Genetics and Microbiology, where his studies focus on the mechanisms involved in the regulation of innate immune responses against bacterial infections. Recent studies from his laboratory highlight the importance of the nervous system in the regulation of innate immune responses. Using genetic and genomic approaches, he was able to demonstrate that specific neurons can regulate innate immunity. His laboratory is currently studying a number of signaling molecules that can be used by the nervous and immune system to communicate to each other.