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. Increasing evidence indicates that immune responses are rapidly coordinated by neural circuits that operate reflexively. 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. This proposal describes experiments designed to elucidate the mechanism by which the nervous system regulates innate immunity. Using the nematode Caenorhabditis elegans, we have recently demonstrated that innate immunity is not only regulated at the cell autonomous level, but also at the cell non-autonomous level through neurons expressing G-protein-coupled receptors. More specifically, we found that NPR-1, a GPCR similar to mammalian neuropeptide Y receptors, participates in a neural circuit that controls the p38/PMK-1 MAPK pathway in C. elegans. Additional studies from our laboratory indicate that OCTR-1, which is an adrenergic GPCR for octopamine expressed in the nervous system, controls the p38/PMK-1 pathway and unfolded response pathways that are expressed in non-neuronal tissues and that are necessary to alleviate the increased demand on protein folding during immune activation. In this proposal specifically, we will use a variety of molecular and genetic techniques to explore the general hypothesis that the nervous system regulates immune homeostasis during host response to pathogen infections at the whole animal level. Given the conserved nature of innate immune responses and of GPCR-mediated signaling in the nervous system, the proposed studies should lead to a better understanding of some of the mechanisms by which the metazoan nervous and innate immune systems influence each other.

Public Health Relevance

The systemic control of innate immunity is critical because inflammation accounts for the major physiological, metabolic, and pathological responses to infections. 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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
2R01GM070977-10
Application #
8585623
Study Section
Special Emphasis Panel (ZRG1-MDCN-B (04))
Program Officer
Dunsmore, Sarah
Project Start
2004-09-30
Project End
2017-08-31
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
10
Fiscal Year
2013
Total Cost
$336,721
Indirect Cost
$119,371
Name
Duke University
Department
Genetics
Type
Schools of Medicine
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705
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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