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.
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.
|Cao, Xiou; Aballay, Alejandro (2016) Neural Inhibition of Dopaminergic Signaling Enhances Immunity in a Cell-Non-autonomous Manner. Curr Biol 26:2329-34|
|Wu, Qiuli; Cao, Xiou; Yan, Dong et al. (2015) Genetic Screen Reveals Link between the Maternal Effect Sterile Gene mes-1 and Pseudomonas aeruginosa-induced Neurodegeneration in Caenorhabditis elegans. J Biol Chem 290:29231-9|
|Cai, Yun; Cao, Xiou; Aballay, Alejandro (2014) Whole-animal chemical screen identifies colistin as a new immunomodulator that targets conserved pathways. MBio 5:|
|Head, Brian; Aballay, Alejandro (2014) Recovery from an acute infection in C. elegans requires the GATA transcription factor ELT-2. PLoS Genet 10:e1004609|
|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; Liu, Yiyong; Aballay, Alejandro (2012) Organismal regulation of XBP-1-mediated unfolded protein response during development and immune activation. EMBO Rep 13:855-60|
|Singh, Varsha; Aballay, Alejandro (2012) Endoplasmic reticulum stress pathway required for immune homeostasis is neurally controlled by arrestin-1. J Biol Chem 287:33191-7|
|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|
Showing the most recent 10 out of 20 publications