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SCMM scientists identify pathway for airway remodeling produced by repetitive viral infections.

Respiratory viral infections and allergen exposures are frequent causes for exacerbations of chronic obstructive lung disease. Recurrent airway infections are associated with progressive declines in lung function. Work by investigators in the SCMM have contributed to the understanding that specialized pattern recognition receptors detect the presence of viral pathogens and initiate protective host inflammation by triggering activation of intracellular signaling pathway known as the innate response. One of the major arms of this pathway is the activation of the cytoplasmic nuclear factor kB (NFkB)/RelA transcription factor; RelA forms a complex with Bromodomain containing protein 4 (BRD4). The RelA•BRD4 complex produces rapid expression of otherwise inactive genes maintained in an open chromatin configuration through a process known as transcriptional elongation. BRD4 is an essential mediator of RelA induced transcriptional elongation, by producing phosphorylation of RNA Pol II and acetylating specific histone residues. Although the acute inflammatory response is important, prolonged activation of this pathway produces irreversible airway remodeling through mechanisms that have not been fully understood.

In a series of studies, SCMM investigators have applied systems levels studies to understand how prolonged activation of the RelA-BRD4 pathway produces chronic remodeling, epithelial cell state changes and airway fibrosis. These studies have elucidated the central role of RelA-BRD4 in chromatin reprogramming mediating mesenchymal state changes, rewiring of the kinome and reprogramming inflammatory genes to be hyperinducible. Modification of the RelA-BRD4 pathway has been enabled through structure-based drug design. This group has discovered small molecule BRD4 inhibitors that show promise to interfere with acute viral inflammation as well as reduce its chronic fibrotic sequelae.

References:

  1. 1.Tian B, Yang J, Zhao Y, Ivanciuc T, Sun H, Garofalo RP, Brasier AR. Bromodomain Containing 4 (BRD4) Couples NFkB/RelA With Airway Inflammation And The IRF-RIG-I Amplification Loop In Respiratory Syncytial Virus Infection Journal of Virology. 2017;in press:PMID: 28077651. doi: doi: 10.1128/JVI.00007-17
  2. 2.Yang J, Tian B, Brasier AR. Targeting Chromatin Remodeling in Inflammation and Fibrosis. In: Donev R, editor. Advances in protein chemistry and structural biology: Elsevier; 2017.
  3. 3.Liu Z, Wang P, Chen H, Wold E, Tian B, Brasier AR, Zhou J. Drug Discovery Targeting Bromodomain-Containing Protein 4 (BRD4). Journal of Medical Chemistry. 2017;in press.
  4. 4.Tian B, Zhao Y, Sun H, Zhang Y, Yang J, Brasier AR. BRD4 Mediates NFkB-dependent Epithelial-Mesenchymal Transition and Pulmonary Fibrosis via Transcriptional Elongation. The American Journal of Physiology -Lung Cellular and Molecular Physiology 2016;311(6):L1183-L201. doi: 10.1152/ajplung.00224.2016; PMCID: PMC5206405.
  5. 5.Zhao Y, Tian B, Sadygov RG, Zhang Y, Brasier AR. Integrative proteomic analysis reveals reprograming tumor necrosis factor signaling in epithelial mesenchymal transition. J Proteomics. 2016;148:126-38. Epub 2016/07/28. doi: 10.1016/j.jprot.2016.07.014. PubMed PMID: 27461979.
  6. 6.Tian B, Patrikeev I, Ochoa L, Vargas G, Belanger KK, Litvinov J, Boldogh I, Ameredes BT, Motamedi M, Brasier AR. NFkappaB Mediates Mesenchymal Transition, Remodeling and Pulmonary Fibrosis in Response to Chronic Inflammation by Viral RNA Patterns. Am J Respir Cell Mol Biol. 2016. Epub 2016/12/03. doi: 10.1165/rcmb.2016-0259OC. PubMed PMID: 27911568.
  7. 7.Aguilera-Aguirre L, Hosoki K, Bacsi A, Radak Z, Sur S, Hegde ML, Tian B, Saavedra-Molina A, Brasier AR, Ba X, Boldogh I. Whole transcriptome analysis reveals a role for OGG1-initiated DNA repair signaling in airway remodeling. Free Radic Biol Med. 2015;89:20-33. doi: 10.1016/j.freeradbiomed.2015.07.007. PubMed PMID: 26187872.
  8. 8.Ijaz T, Pazdrak K, Kalita M, Konig R, Choudhary S, Tian B, Boldogh I, Brasier AR. Systems Biology Approaches To Understanding Epithelial Mesenchymal Transition (EMT) In Mucosal Remodeling And Signaling In Asthma. World Allergy Organization Journal. 2014;7(1):13; PMCID: PMC4068075.
SCMM scientists elucidate epigenetic pathways controlling mucosal innate anti-viral response in chronic airway remodeling.

Asthma is a major public health concern affecting ~ 4% of the population worldwide.This chronic disease is associated with epithelial cell injury, producing a growth factor response that disrupts its normal barrier function. Maintenance of the e pithelial barrier is important because it forms the first point of entry for viral respiratory tract infections and plays a major role in initiating a protective host response. Several studies have found that a common cold virus, rhinovirus, replicates more efficiently in asthmatic epithelium in the setting of reduced anti-viral interferon production. The mechanistic relationship between airway remodeling and defective innate immunity is not understood.

SCMM investigators examined the mechanism for enhanced viral replication in chronically injured airway epithelial cells. They discovered that chronic injury reprograms the anti-viral response mediated through the protective interferon regulatory factor (IRF1) signaling pathway. Their studies demonstrate that epithelial injury produces a defect in otherwise highly inducible IRF1 expression. This defect is due to epigenetic remodeling of silencing histones on the IRF1 gene that occludes the upstream transcription factors, RelA and IRF3, from being able to bind to the IRF1 promoter. Their work further demonstrated that the Zinc Finger E-Box Binding Homeobox 1 (ZEB1) transcriptional modulator silences IRF1 through by forming repressive H3K27(me3) marks.

This exciting study demonstrates how airway remodeling/fibrosis produces a defective mucosal antiviral response. This work is the first to demonstrate epigenetic regulation of the innate pathway through silencing specific arms of the anti-viral innate response. Elucidation of this pathway suggests that epigenetic regulators may be used to restore normal anti-viral responses in severe asthma.

References:

  1. Yang J, Tian B, Sun H, Garofalo R, Brasier AR: ZEB1 mediated epigenetic silencing of IRF1 dysregulates type III interferon responses to respiratory virus infection in epithelial to mesenchymal transition. Nature Microbiology 2017, 17086 (2017) | DOI: 10.1038/nmicrobiol.2017.1086
  2. Yang J, Tian B, Brasier AR. Targeting Chromatin Remodeling in Inflammation and Fibrosis. In: Donev R, editor. Advances in protein chemistry and structural biology: Elsevier; 2017.