Innate immunity serves as the first line of defense used by metazoans to prevent microbial infections. This immune response to invading microorganisms needs to be fine-tuned to prevent deleterious deficiencies or excesses in the response. There is a large body of evidence indicating that the metazoan nervous system plays a key role in the modulation of innate immunity to regulate host defenses. However, given the complexity of the nervous and immune systems of mammals, the precise mechanisms by which the two systems influence each other remain understudied. The nematode Caenorhabditis elegans is a well suited model to study the functional connection between neuronal function and innate immunity in vivo. Our laboratory has shown that in C. elegans certain G-protein coupled receptors (GPCRs) and at least five neurons actively regulate innate immune pathways in response to pathogen infection. This indicates that cell non-autonomous signals from different neurons may act on non-neural tissues to regulate innate immunity. Our hypothesis that GPCRs participate in neural circuits that receive inputs from either pathogens or infected sites and integrate them to coordinate appropriate immune responses. To gain insights into the effects of pathogen infection on neuron activity, we are studying the effects of neural ablation and neural activation on the C. elegans innate immune response to different human Gram-negative and Gram-positive pathogens. Our work will lead to a better understanding of the mechanisms by which the metazoan nervous system and innate immune system influence each other and will potentially unveil targets for therapeutic intervention during disease.