The innate immune system is the first line of defense against invading microorganisms. When the innate immune system fails to be activated, lethal infection ensues. Conversely, the inappropriate activation of innate immunity can lead to a variety of illnesses, including sepsis, rheumatoid arthritis and lupus. Insects rely solely on an innate immune response to combat pathogens. The study of innate immunity in Drosophila, a genetically tractable organism for which advanced genetic methods are available, allows for the rapid progress in the study of innate immunity in the absence of the confounding influence of the adaptive immune response. The study of Drosophila immunity has resulted in important contributions to our understanding of immunity in humans, such as the identification of Toll receptors. The long-term goal of this proposal is to elucidate the molecular mechanisms responsible for the recognition of gram-negative bacteria and the subsequent activation of the signal transduction pathways which culminate in the expression of antimicrobial peptide genes in Drosophila. The IMD signal transduction pathway is critical for immune activation and survival following gram-negative infection. The proposed experiments will characterize the gram-negative bacterial products that are recognized by the receptor PGRP-LC, and uncover the mechanisms by which PGRP-LC activates the IMD intracellular signaling pathway. This pathway requires the kinases dTAK1 and Drosophila IKK as well as the caspase Dredd, and culminates in the activation, by caspase-mediate cleavage, of the Drosophila NF-kB homolog Relish. We propose to investigate the mechanism(s) by which the cleavage of Relish is controlled by IKK-mediated phosphorylation. We will characterize a parallel signal transduction pathway, also activated via PGRP-LC, that involves JNK kinas activation, and results in the expression of a number of novel genes likely to be involved in host defense. We believe that the successful completion of our Aims is likely to lead to a better understanding of the innate immune response, in humans and flies. Such an understanding is critical to our ability to devise more effective therapies against inflammatory disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI060025-07
Application #
7754458
Study Section
Special Emphasis Panel (ZRG1-SSS-F (01))
Program Officer
Leitner, Wolfgang W
Project Start
2004-02-15
Project End
2011-07-31
Budget Start
2010-02-01
Budget End
2011-01-31
Support Year
7
Fiscal Year
2010
Total Cost
$329,440
Indirect Cost
Name
University of Massachusetts Medical School Worcester
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
603847393
City
Worcester
State
MA
Country
United States
Zip Code
01655
Kleino, Anni; Ramia, Nancy F; Bozkurt, Gunes et al. (2017) Peptidoglycan-Sensing Receptors Trigger the Formation of Functional Amyloids of the Adaptor Protein Imd to Initiate Drosophila NF-?B Signaling. Immunity 47:635-647.e6
Chen, Li; Paquette, Nicholas; Mamoor, Shahan et al. (2017) Innate immune signaling in Drosophila is regulated by transforming growth factor ? (TGF?)-activated kinase (Tak1)-triggered ubiquitin editing. J Biol Chem 292:8738-8749
Paik, Donggi; Monahan, Amanda; Caffrey, Daniel R et al. (2017) SLC46 Family Transporters Facilitate Cytosolic Innate Immune Recognition of Monomeric Peptidoglycans. J Immunol 199:263-270
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Gulia-Nuss, Monika; Nuss, Andrew B; Meyer, Jason M et al. (2016) Genomic insights into the Ixodes scapularis tick vector of Lyme disease. Nat Commun 7:10507
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Ganesan, Sandhya; Rathinam, Vijay A K; Bossaller, Lukas et al. (2014) Caspase-8 modulates dectin-1 and complement receptor 3-driven IL-1? production in response to ?-glucans and the fungal pathogen, Candida albicans. J Immunol 193:2519-2530
Weng, Dan; Marty-Roix, Robyn; Ganesan, Sandhya et al. (2014) Caspase-8 and RIP kinases regulate bacteria-induced innate immune responses and cell death. Proc Natl Acad Sci U S A 111:7391-6
Kim, Chan-Hee; Paik, Donggi; Rus, Florentina et al. (2014) The caspase-8 homolog Dredd cleaves Imd and Relish but is not inhibited by p35. J Biol Chem 289:20092-101
Kleino, Anni; Silverman, Neal (2014) The Drosophila IMD pathway in the activation of the humoral immune response. Dev Comp Immunol 42:25-35

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