Recent studies have revealed that key signaling pathways of mammalian innate immunity have ancient evolutionary origins evident in the immune response cascades of invertebrate organisms such as insects and nematodes. The long-term goal of this project is to carry out the comprehensive analysis of innate immunity in C. elegans, with the anticipation that the systematic study of immunity in this genetically tractable host organism will illuminate evolutionarily conserved mechanisms of pathogen recognition and defense in mammalian innate immunity. We have initiated a multi-pronged functional genomic approach to the study of C. elegans immunity. We identified a requirement for a conserved PMK-1 p38 MARK pathway and TIR-1, a conserved Toll-lnterleukin-1-Receptor (TIR) domain adaptor protein that appears to function upstream of the PMK-1 pathway. We have used genome-wide microarray analysis to identify candidate immune effectors under the regulation of the PMK-1 pathway. We have identified additional candidate immune signaling components that may converge on PMK-1 from a systematic RNAi-based screen. Based on these data, we have developed the specific hypothesis of this proposal, which is that pathogen infection activates a TIR-1-PMK-1 signaling cascade that confers immunity through the regulation of secreted antimicrobial factors at the site of infection. We propose three specific aims to define the mechanisms by which the TIR-1-PMK-1 pathway confers immunity. First, we will determine whether the PMK-1 MAPK pathway acts locally in cells at the site of infection or systemically in pathogen defense. Second, we will define the mechanisms regulated by PMK-1 that confer pathogen resistance by functional analysis of PMK-1 transcriptional targets. Third, we will define the mechanism of TIR-1 activation of the PMK-1 MAPK pathway in response to pathogen. We will dissect the functional domains of the TIR-1 protein and characterize interacting proteins, assign candidate genes from our RNAi screen to the TIR-1-PMK-1 pathway by genetic interaction analysis, and systematically identify additional genes required for TIR-1 activation of the PMK-1 pathway using complementary genetic methods. In summary, the p38 MAPK pathway constitutes a critical mediator of innate immunity that has been conserved from worms to humans. We anticipate that the genetic dissection, of the mechanisms of immunity mediated by the p38 MAPK ortholog, PMK-1, will provide important insights into the mechanisms of mammalian innate immunity, including the role of the mammalian TIR-1 ortholog, SARM.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM084477-05
Application #
8116015
Study Section
Innate Immunity and Inflammation Study Section (III)
Program Officer
Dunsmore, Sarah
Project Start
2007-09-01
Project End
2013-07-31
Budget Start
2011-08-01
Budget End
2013-07-31
Support Year
5
Fiscal Year
2011
Total Cost
$288,150
Indirect Cost
Name
Massachusetts Institute of Technology
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
001425594
City
Cambridge
State
MA
Country
United States
Zip Code
02139
Fletcher, Marissa; Kim, Dennis H (2017) Age-Dependent Neuroendocrine Signaling from Sensory Neurons Modulates the Effect of Dietary Restriction on Longevity of Caenorhabditis elegans. PLoS Genet 13:e1006544
Hilbert, Zoë A; Kim, Dennis H (2017) Sexually dimorphic control of gene expression in sensory neurons regulates decision-making behavior in C. elegans. Elife 6:
Kulalert, Warakorn; Sadeeshkumar, Harini; Zhang, Ying K et al. (2017) Molecular Determinants of the Regulation of Development and Metabolism by Neuronal eIF2? Phosphorylation in Caenorhabditis elegans. Genetics 206:251-263
Meisel, Joshua D; Kim, Dennis H (2016) Inhibition of Lithium-Sensitive Phosphatase BPNT-1 Causes Selective Neuronal Dysfunction in C. elegans. Curr Biol 26:1922-8
Cattie, Douglas J; Richardson, Claire E; Reddy, Kirthi C et al. (2016) Mutations in Nonessential eIF3k and eIF3l Genes Confer Lifespan Extension and Enhanced Resistance to ER Stress in Caenorhabditis elegans. PLoS Genet 12:e1006326
Pagano, Daniel J; Kingston, Elena R; Kim, Dennis H (2015) Tissue expression pattern of PMK-2 p38 MAPK is established by the miR-58 family in C. elegans. PLoS Genet 11:e1004997
Meisel, Joshua D; Panda, Oishika; Mahanti, Parag et al. (2014) Chemosensation of bacterial secondary metabolites modulates neuroendocrine signaling and behavior of C. elegans. Cell 159:267-80
Kulalert, Warakorn; Kim, Dennis H (2013) The unfolded protein response in a pair of sensory neurons promotes entry of C. elegans into dauer diapause. Curr Biol 23:2540-5
Chang, Howard C; Paek, Jennifer; Kim, Dennis H (2011) Natural polymorphisms in C. elegans HECW-1 E3 ligase affect pathogen avoidance behaviour. Nature 480:525-9
Youngman, Matthew J; Rogers, Zoë N; Kim, Dennis H (2011) A decline in p38 MAPK signaling underlies immunosenescence in Caenorhabditis elegans. PLoS Genet 7:e1002082

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