This proposal describes experiments designed to elucidate the mechanism by which the nervous system regulates innate immunity in response to pathogen infection. Our work in Caenorhabditis elegans has led to the identification of mutants that exhibit aberrant responses when infected with different pathogens. Analysis of these C. elegans mutants deficient in immune responses is clarifying the roles of a variety of interacting and intersecting genetic pathways involved in immune responses highly conserved across species, including humans. The latest studies from our laboratory indicate that innate immunity in C. elegans is regulated by neurons expressing NPR-1, which is a G-protein-coupled receptor related to mammalian neuropeptide Y receptors. Our studies have demonstrated that a neural circuit involving NPR-1 functions to suppress innate immune responses. The immune inhibitory function requires a cyclic GMP-gated ion channel encoded by tax-2 and tax-4 as well as the soluble guanylate cyclase GCY-35. Furthermore, we showed that npr-1- and gcy-35-expressing sensory neurons actively suppress immune responses of non-neuronal tissues. A full-genome microarray analysis on animals with altered neural function due to mutation in npr-1 showed enrichment in genes that are markers of innate immune responses, including those regulated by a conserved PMK-1/p38 mitogen-activated protein kinase signaling pathway. This proposal will continue our studies utilizing a C. elegans model to clarify the role of the nervous system in the regulation of innate immunity against bacterial pathogens. We hypothesize that G-protein coupled receptors (GPCRs) may participate in neural circuits that receive inputs from either pathogens or infected sites and integrate them to coordinate appropriate innate immune responses. There are three specific aims: 1) Identification of neurons expressing GPCRs that regulate innate immunity. 2) Dissection of the neural circuit that regulates innate immunity. 3) Identification and characterization of signals involved in neural- immune communications. The proposed studies will serve as a roadmap to understand the mechanisms by which the nervous and immune systems communicate through bidirectional signals. Given the conserved nature of neural communications and innate immune responses, we expect our work will lead to a better understanding of the mechanisms by which the metazoan nervous and innate immune systems influence each other.

Public Health Relevance

We plan to continue our studies to clarify the role of the nervous system in the regulation of innate immune responses against bacterial pathogens. A better understanding of the neural-immune communication could lead to new therapeutic targets for diseases involving a deficient innate immune system.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Neuroendocrinology, Neuroimmunology, and Behavior Study Section (NNB)
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Dunsmore, Sarah
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Duke University
Schools of Medicine
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Aballay, Alejandro (2013) Role of the nervous system in the control of proteostasis during innate immune activation: insights from C. elegans. PLoS Pathog 9:e1003433
Sun, Jingru; Singh, Varsha; Kajino-Sakamoto, Rie et al. (2011) Neuronal GPCR controls innate immunity by regulating noncanonical unfolded protein response genes. Science 332:729-32
TeKippe, Michael; Aballay, Alejandro (2010) C. elegans germline-deficient mutants respond to pathogen infection using shared and distinct mechanisms. PLoS One 5:e11777
Bolz, Devin D; Tenor, Jennifer L; Aballay, Alejandro (2010) A conserved PMK-1/p38 MAPK is required in caenorhabditis elegans tissue-specific immune response to Yersinia pestis infection. J Biol Chem 285:10832-40
Singh, Varsha; Aballay, Alejandro (2009) Regulation of DAF-16-mediated Innate Immunity in Caenorhabditis elegans. J Biol Chem 284:35580-7
Aballay, Alejandro (2009) Neural regulation of immunity: role of NPR-1 in pathogen avoidance and regulation of innate immunity. Cell Cycle 8:966-9
Fuhrman, Laura E; Goel, Ajay Kumar; Smith, Jason et al. (2009) Nucleolar proteins suppress Caenorhabditis elegans innate immunity by inhibiting p53/CEP-1. PLoS Genet 5:e1000657
Haskins, Kylie A; Russell, Jonathan F; Gaddis, Nathan et al. (2008) Unfolded protein response genes regulated by CED-1 are required for Caenorhabditis elegans innate immunity. Dev Cell 15:87-97
Fuhrman, Laura E; Shianna, Kevin V; Aballay, Alejandro (2008) High-throughput isolation and mapping of C. elegans mutants susceptible to pathogen infection. PLoS One 3:e2882
Styer, Katie L; Singh, Varsha; Macosko, Evan et al. (2008) Innate immunity in Caenorhabditis elegans is regulated by neurons expressing NPR-1/GPCR. Science 322:460-4

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