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 (PRRs) that recognize conserved molecular patterns characteristic of the microbe, which are not found within the host. The Toll-like receptors (TLRs) and the RIG-I-like receptors (RLRs) are the PRRs that detect viruses. These receptors initiate anti-viral responses principally by inducing type I interferons. The tight regulation of type I IFNs is critical since overproduction of the cytokine can contribute significantly to autoimmune disease;thus the balance between health and disease is determined by exquisite regulation of this pathway. The transcription factor IRF7 is a "master regulator" of systemic type 1 IFN responses. While much is known about the mechanisms by which IRF7 is activated little is known about its negative regulation. Systems biology approaches have enabled us to identify at least two negative regulators of the IRF7 pathway: the transcription factor Foxo3 that regulates IRF7 at a transcriptional level and microRNA-144 (miR-144) that regulates the IRF7 network post-transcriptionally. We also have evidence that at least one additional miRNA regulates IRF7. This proposal aims to clarify the molecular mechanisms by which Foxo3 and miR-144 control IRF7. It also aims to identify the unknown IRF7-regulating miRNAs using a high throughput screen. Systems approaches will then be used to integrate Foxo3 and the miRNAs into a global IRF7 regulatory network. Finally, we will examine the in vivo relevance of the IRF7- FOXO3-miRNA regulatory circuit in a mouse model of VSV infection.
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. However, these molecules are a two-edged sword. When they function incorrectly they lead to inflammatory and autoimmune diseases. Understanding how this happens will lead to the design and production of better drugs for diseases such as rheumatoid arthritis.
|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|
|Schoggins, John W; MacDuff, Donna A; Imanaka, Naoko et al. (2015) Corrigendum: Pan-viral specificity of IFN-induced genes reveals new roles for cGAS in innate immunity. Nature 525:144|
|Zak, Daniel E; Aderem, Alan (2015) Systems integration of innate and adaptive immunity. Vaccine 33:5241-8|
|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|
Showing the most recent 10 out of 52 publications