Transcriptomics in lung tissue upon respiratory syncytial virus infection reveals aging as important modulator of immune activation and matrix maintenance

Abstract

Aging poses an increased risk of severe infection by respiratory syncytial virus (RSV). The many different biological pathways comprising the response to infection in lungs that are influenced by aging are complex and remain to be defined more thoroughly. Towards finding new directions in research on aging, we aimed to define biological pathways in the acute response to RSV that are affected in the lungs by aging. We therefore profiled the full transcriptome of lung tissue of mice prior to and during RSV infection both at young and old age. In the absence of RSV, we found aging to downregulate genes that are involved in constitution of the extracellular matrix. Moreover, uninfected old mice showed elevated expression of pathways that resemble injury, metabolic aberrations, and disorders mediated by functions of the immune system that were induced at young age only by an exogenous trigger like RSV. Furthermore, infection by RSV mounted stronger activation of anti-viral type-I interferon pathways at old age. Despite such exaggerated anti-viral responses, old mice showed reduced control of virus. Altogether, our findings emphasize important roles in aging-related susceptibility to respiratory disease for extracellular matrix dysfunctions and dysregulated immune activation in lungs.

Experimental challenge with bovine respiratory syncytial virus in dairy calves: bronchial lymph node transcriptome response

“…BRSV is closely related to human RSV, and induces similar pathologies 15,37 and alterations in host gene expression. Genes involved in the type 1 interferon antiviral response, including BP1, RSAD2, MX2, MX1, ISG15, IRF7, IFITM3, IFIT3, IFIT2, IFIT1, IFIH1, IFI44 , which were upregulated in the lungs of C57BL/6 mice, in response to infection with RSV 54 , were also up-regulated in the calves challenged with BRSV in the present study. Therefore, the gene expression changes induced by BRSV infection detected in this study may provide an insight into the human bronchial lymph node transcriptional response to RSV.…”

Role of Aging and the Immune Response to Respiratory Viral Infections: Potential Implications for COVID-19

“…Microarray analysis of lung tissue from young and aged mice infected with RSV show that as early as 2 d postinfection, aged mice exhibit higher levels of cytokine-related transcripts and IFN-related transcripts, such as Irf7, Oasl7 Ccl8, and Cxcl9 compared with young mice (67). This study also showed that before RSV infection, aging leads to upregulation of 113 of the total 373 significantly regulated immune-modulating genes in the lung, suggesting that increased morbidity with aging during RSV may be partially due to an elevated basal inflammatory response, also termed "inflammaging" (19,67). Even with higher levels of antiviral type I IFN signaling, aged mice still exhibit higher levels of viral load (65,67).…”

Lung transcriptomic clock predicts premature aging in cigarette smoke-exposed mice

“…For example, irradiated young mice exhibit lung transcriptomic profiles similar to unirradiated older mice [20]. Similarly, infection of young mice by respiratory syncytial virus induces transcriptomic alterations similar to those observed in uninfected old mice [16].…”

“…Over the last decade, a massive number of transcriptomes have been generated, primarily by microarrays [12], in order to identify markers of aging and to understand the underlying mechanisms of aging processes. These studies revealed a number of common features for age-related transcriptomic changes, including the upregulation [13,14] of genes involved in inflammation and stress response and the downregulation of genes associated with extracellular matrix constitution and metabolism [15,16].…”