The innate immune system is the first line of defense against pathogens. Innate immune cells lack the exquisite specificity of the adaptive immune system, yet in order to respond in a measured way they must be able to tailor their response to the specific pathogen. These cells have therefore evolved pattern recognition receptors including the Toll-like receptors (TLRs) that recognize conserved molecular patterns characteristic of the microbe, which are not found within the host. While much is known about the mechanisms through which TLRs mediate immune responses, a number of critical questions remain unanswered. Central to these is a complete knowledge of all the components of the TLR signaling pathways and an understanding of how the architectural arrangement of these components leads to the appropriate coordination of host defense. We have utilized the tools of systems biology to discover Sharpin, a novel component of TLR signaling, and our preliminary studies of the protein have altered our understanding of the architecture of the TLR pathway. We have demonstrated that Sharpin acts at the level of the NEMO-containing IKK complex and controls a novel branch point in the TLR2/NF-?B pathway that is necessary for the production of Th1 cytokines. In this proposal, we will: 1. Determine the mechanism by which Sharpin influences transcriptional responses of TLR- dependent genes through epigenetic modification of chromatin structure and enhanceosome formation. 2. Delineate the manner by which Sharpin transduces TLR2/MyD88 signals through the IKK complex to regulate transcriptional responses. 3. Determine the role of Sharpin in controlling innate and adaptive immune responses to bacterial pathogens in vivo. The proposed study will advance our knowledge of the TLR2/MyD88 pathway, NF-?B activation, epigenetic regulation of innate immune genes, and mechanisms underlying the instruction of adaptive responses by innate immune cells.

Public Health Relevance

The proteins that are being investigated have a pivotal role in regulating the immune response in people. They instruct the body to effectively combat infectious disease, and an understanding of their function will permit us to make better vaccines and drugs.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
2R01AI025032-25A1
Application #
8371935
Study Section
Innate Immunity and Inflammation Study Section (III)
Program Officer
Davidson, Wendy F
Project Start
1987-07-01
Project End
2017-04-30
Budget Start
2012-05-01
Budget End
2013-04-30
Support Year
25
Fiscal Year
2012
Total Cost
$668,316
Indirect Cost
$290,410
Name
Seattle Biomedical Research Institute
Department
Type
DUNS #
070967955
City
Seattle
State
WA
Country
United States
Zip Code
98109
Rothchild, Alissa C; Sissons, James R; Shafiani, Shahin et al. (2016) MiR-155-regulated molecular network orchestrates cell fate in the innate and adaptive immune response to Mycobacterium tuberculosis. Proc Natl Acad Sci U S A 113:E6172-E6181
Gillespie, Mark A; Gold, Elizabeth S; Ramsey, Stephen A et al. (2015) An LXR-NCOA5 gene regulatory complex directs inflammatory crosstalk-dependent repression of macrophage cholesterol efflux. EMBO J 34:1244-58
Zak, Daniel E; Aderem, Alan (2015) Systems integration of innate and adaptive immunity. Vaccine 33:5241-8
Aachoui, Youssef; Kajiwara, Yuji; Leaf, Irina A et al. (2015) Canonical Inflammasomes Drive IFN-γ to Prime Caspase-11 in Defense against a Cytosol-Invasive Bacterium. Cell Host Microbe 18:320-32
Schliehe, Christopher; Flynn, Elizabeth K; Vilagos, Bojan et al. (2015) The methyltransferase Setdb2 mediates virus-induced susceptibility to bacterial superinfection. Nat Immunol 16:67-74
Knijnenburg, Theo A; Ramsey, Stephen A; Berman, Benjamin P et al. (2014) Multiscale representation of genomic signals. Nat Methods 11:689-94
Gold, Elizabeth S; Diercks, Alan H; Podolsky, Irina et al. (2014) 25-Hydroxycholesterol acts as an amplifier of inflammatory signaling. Proc Natl Acad Sci U S A 111:10666-71
Zak, Daniel E; Tam, Vincent C; Aderem, Alan (2014) Systems-level analysis of innate immunity. Annu Rev Immunol 32:547-77
Ramsey, Stephen A; Vengrenyuk, Yuliya; Menon, Prashanthi et al. (2014) Epigenome-guided analysis of the transcriptome of plaque macrophages during atherosclerosis regression reveals activation of the Wnt signaling pathway. PLoS Genet 10:e1004828
Schoggins, John W; MacDuff, Donna A; Imanaka, Naoko et al. (2014) Pan-viral specificity of IFN-induced genes reveals new roles for cGAS in innate immunity. Nature 505:691-5

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