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

Abstract

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.Viruses 2020, 12, 472 2 of 17 spread into the lower airways produces lower respiratory tract infection (LRTI), whose clinical features include bronchiolitis and pneumonia. Pathologically, LRTI is associated with epithelial giant cell formation, necrosis, sloughing, producing mucous plugging, ventilation-perfusion mismatching, and acute hypoxic respiratory failure [2][3][4]. The findings that the initial clinical manifestations of hypoxia are correlated with high viral titers and epithelial-derived cytokines [5,6] indicates that RSV activation of the IIR plays an important component of early disease manifestations.Observational studies of naturally occurring RSV infections in humans suggest that acute infection produces an initial neutrophilic airway inflammation [7], followed by a CD8+ T-cell response important in viral clearance (reviewed in [8]). Because protective IgA antibodies wane six months after...

Respiratory Syncytial Virus Infection Induces Chromatin Remodeling to Activate Growth Factor and Extracellular Matrix Secretion Pathways

“…With promoters in an open chromatin environment engaged with RNA Pol II, activated NFκB, STAT, and IRF are able to induce high level of expression in response to RSV infection. Together, these data indicate that promoters expressing this subgroup of Th2 cytokines are primed for rapid transcriptional elongation, a major mode of cytokine activation in response to the innate immune response [13,28].…”

“…These cells also maintain a highly differentiated epithelial phenotype without entering senescence in cell culture [15], making this model robust for profiling chromatin landscape during cell state transitions [14,26]. Our previous work shows that hSAECs support RSV replication, and activate innate signaling in a dose and MOI-dependent manner [13,27,28]. At a multiplicity of infection (MOI) of 1, hSAECs express a time-dependent activation of chemokines, cytokines and anti-viral IFNs that peak at 24 h without evidence of cell death [11].…”

“…Mentioned earlier, RSV replicates for up to 28 d in the lower respiratory tract in viral challenge models [12], where chronic inflammation and signals may be generated to promote disruption of the epithelial barrier and structural remodeling. Viral infection induced EMT induces secretion of IL6, TGFβ, and other growth factors that trigger expansion of subepithelial myofibroblasts [13]. Myofibroblasts are αSMA + /COL1 + and are thought to be major sources of ECM deposition, contributing to lamina reticularis expansion and interstitial fibrosis [47].…”

“…In human RSV challenge studies, although only mild disease is observed clinically in adult volunteers, RSV spreads to the lower airway where it produces prolonged mucosal inflammation [ 12 ]. In contrast to epithelial cells from the conducting airways, lower airway bronchiolar cells play a key role in the pathogenesis of RSV-induced inflammation and obstruction [ 13 ]. In mice, small airway epithelial cells of the distal bronchiole play a central role in RSV-induced neutrophilic inflammation, mucous production, and obstruction [ 7 ].…”

A New Family of Fused Azolo[1,5-a]pteridines and Azolo[5,1-b]purines

“… 4 There are experimental data on anti-inflammatory and antibacterial activities of pyrazolo[4.3- g ]pteridines; 4b 7-amino-azolo[4,3- f ]- and [1,5- f ]pteridinones have been established to be antitumour agents, 4c while 4,5-dihydro[1,2,4]triazolo[4,3- f ]pteridines are known to act as inhibitors of the BRD4 chromatin-binding protein, 5 which is a biological target for many diseases, including cancer, 6 inflammation, 7 diabetes, 8 and viral infections. 9 These data demonstrate an extremely wide range of plausible therapeutic applications of these compounds. 4d However, the data on the synthesis and biological activity of the azolo[1,5- a ]pteridines remain to be scarcely available.…”