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.
Highlights
Respiratory syncytial virus infection is responsible for seasonal upper and lower respiratory tract infections worldwide, causing substantial morbidity
TSLP has a broad variety of target cell responses, its ability to activate plasmacytoid dendritic cell populations and promote T helper 2 (Th2) lymphocyte–predominant inflammation is especially relevant to the pathophysiology of severe lower respiratory tract infection (LRTI) infection
We found that respiratory syncytial virus (RSV)-induced oxidative stress triggers NFκB/Rel Ser 276 phosphorylation, a posttranslational modification stoichiometrically coupled with Lys 310 acetylation recognized by bromodomain containing 4 (BRD4) in the positive transcriptional elongation factor-b (P-TEFb) complex [52]
Summary
Respiratory syncytial virus (RSV) is responsible for seasonal outbreaks of respiratory tract infections worldwide. A focus of the investigations of naturally occurring disease has been on understanding why the adaptive response to RSV is transient These defects may be due to defective formation of memory CD8+ T-cells [9], suppression of activated CD8+ T-cells via PD-L1 [10], or induction of CD8+ T-cell apoptosis [8]. Viral antigen, giant cell formation, and mucosal epithelial sloughing persisted up to 28 days later, lower respiratory tract symptoms were largely absent These findings suggest that even in adults with prior RSV exposure, upper respiratory tract infections (URIs) are associated with asymptomatic viral replication and persistent mucosal inflammation in the lower tract
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