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Non-Coding RNAs and Their Role in Respiratory Syncytial Virus (RSV) and Human Metapneumovirus (hMPV) Infections
Review

RSV Reprograms the CDK9•BRD4 Chromatin Remodeling Complex to Couple Innate Inflammation to Airway Remodeling

Institute for Clinical and Translational Research; University of Wisconsin-Madison School of Medicine and Public Health; Madison, WI 53705, USA
Received: 27 March 2020 / Revised: 17 April 2020 / Accepted: 19 April 2020 / Published: 22 April 2020
(This article belongs to the Special Issue From RSV to hMPV: Role of Innate Immunity in Pathogenesis)
Respiratory syncytial virus infection is responsible for seasonal upper and lower respiratory tract infections worldwide, causing substantial morbidity. Self-inoculation of the virus into the nasopharynx results in epithelial replication and distal spread into the lower respiratory tract. Here, respiratory syncytial virus (RSV) activates sentinel cells important in the host inflammatory response, resulting in epithelial-derived cytokine and interferon (IFN) expression resulting in neutrophilia, whose intensity is associated with disease severity. I will synthesize key findings describing how RSV replication activates intracellular NFκB and IRF signaling cascades controlling the innate immune response (IIR). Recent studies have implicated a central role for Scg1a1+ expressing progenitor cells in IIR, a cell type uniquely primed to induce neutrophilic-, T helper 2 (Th2)-polarizing-, and fibrogenic cytokines that play distinct roles in disease pathogenesis. Molecular studies have linked the positive transcriptional elongation factor-b (P-TEFb), a pleiotrophic chromatin remodeling complex in immediate-early IIR gene expression. Through intrinsic kinase activity of cyclin dependent kinase (CDK) 9 and atypical histone acetyl transferase activity of bromodomain containing protein 4 (BRD4), P-TEFb mediates transcriptional elongation of IIR genes. Unbiased proteomic studies show that the CDK9•BRD4 complex is dynamically reconfigured by the innate response and targets TGFβ-dependent fibrogenic gene networks. Chronic activation of CDK9•BRD4 mediates chromatin remodeling fibrogenic gene networks that cause epithelial mesenchymal transition (EMT). Mesenchymal transitioned epithelial cells elaborate TGFβ and IL6 that function in a paracrine manner to expand the population of subepithelial myofibroblasts. These findings may account for the long-term reduction in pulmonary function in children with severe lower respiratory tract infection (LRTI). Modifying chromatin remodeling properties of the CDK9•BRD4 coactivators may provide a mechanism for reducing post-infectious airway remodeling that are a consequence of severe RSV LRTIs. View Full-Text
Keywords: Airway remodeling; cyclin dependent kinase 9 (CDK9); bromodomain containing protein 4 (BRD4); mesenchymal transition; myofibroblast; epigenetics Airway remodeling; cyclin dependent kinase 9 (CDK9); bromodomain containing protein 4 (BRD4); mesenchymal transition; myofibroblast; epigenetics
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MDPI and ACS Style

Brasier, A.R. RSV Reprograms the CDK9•BRD4 Chromatin Remodeling Complex to Couple Innate Inflammation to Airway Remodeling. Viruses 2020, 12, 472. https://0-doi-org.brum.beds.ac.uk/10.3390/v12040472

AMA Style

Brasier AR. RSV Reprograms the CDK9•BRD4 Chromatin Remodeling Complex to Couple Innate Inflammation to Airway Remodeling. Viruses. 2020; 12(4):472. https://0-doi-org.brum.beds.ac.uk/10.3390/v12040472

Chicago/Turabian Style

Brasier, Allan R. 2020. "RSV Reprograms the CDK9•BRD4 Chromatin Remodeling Complex to Couple Innate Inflammation to Airway Remodeling" Viruses 12, no. 4: 472. https://0-doi-org.brum.beds.ac.uk/10.3390/v12040472

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