Dataset Information

Reduced inflammatory and Th1 transcriptional profiles in adult and geriatric cotton rats infected with respiratory syncytial virus

ABSTRACT: Human respiratory syncytial virus (RSV) is a leading cause of severe respiratory disease in elderly populations. RSV clearance is delayed in individuals over 65 years of age, a finding that is recapitulated in the geriatric cotton rat model. Altered inflammatory responses in elderly populations have been implicated with impaired clearance of several pathogens but remain poorly described for RSV. We performed RNA sequencing (RNA-seq) and pathway analysis on lung tissue of RSV-infected adult and geriatric cotton rats to characterize differential host immune responses between these age groups. No differences in inflammatory gene expression were observed between uninfected adult and geriatric cotton rats. At day 1 post-infection, adult cotton rats expressed higher levels of several cytokines and transcription factors associated with acute inflammation and initiation of a Th1 response, including IFN-β, IL12, and Tbet, compared to geriatric cotton rats. By day 4 post-infection, adult cotton rats additionally expressed higher levels of effector molecules associated with Th1 responses, including IFN-γ. Pathway analysis showed significantly increased activation of several pro-inflammatory pathways in adults, including the Th1 pathway, macrophage classical (M1) activation, and pathogen-induced cytokine signaling. To evaluate lymphocyte Th1/Th2 polarization resulting from RSV infection in both age groups, we stimulated splenocytes with RSV peptides at day 28 post-infection and measured IFN-γ and IL-4 production by ELISA. Splenocytes of all adult cotton rats produced detectable IFN-γ and no IL-4, indicating Th1 polarization. Splenocytes of all geriatric cotton rats produced detectable IL-4, indicating Th2 polarization. Collectively, these results indicate that geriatric cotton rats exhibit impaired generation of a Th1 response and a decreased inflammatory response overall to RSV.

ORGANISM(S): Sigmodon hispidus

PROVIDER: GSE297903 | GEO | 2026/06/01

REPOSITORIES: GEO

ACCESS DATA

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Project description:Inflammation is the natural defensive response of the immune system to an injury or infection and is regulated by small molecule mediators triggering different phases of the inflammatory process. In particular, lipid mediators (LM) and cytokines exhibit crucial regulatory functions in the progression and resolution of inflammation. Macrophages play a central role in this process and can adopt distinct phenotypes with specialized functions depending on their microenvironment: inflammatory M1 macrophages drive inflammation by the release of pro-inflammatory cytokines and LMs, like prostaglandins (PG) and leukotrienes (LT), while resolving M2 macrophages promote inflammation resolution and tissue regeneration by production of anti-inflammatory cytokines and specialized pro resolving mediators (SPM). Aging is associated with chronic and unresolved, low-grade inflammation (“inflammaging”) and aging-related dysfunction of macrophages in the resolution of inflammation and tissue maintenance has been reported. Yet, the underlying molecular mechanisms and functional consequences of latter processes remain poorly understood. Here, we show that polarization of peritoneal macrophages (PM) from geriatric mice towards an M2-like phenotype is impaired versus adult mice, resulting in aberrant LM formation and cytokine release. In PMs isolated from adult mice (PM-A) we observed a shift in LM formation from PGs and LTs to SPMs already after 4 h of polarization towards M2 with interleukin (IL) 4. In contrast, PMs from geriatric mice (PM-G) produced mainly LTs and PGs upon polarization. This pattern persists over the course of 48 h of polarization. Proteomic profiling revealed that polarization of PM A towards M2 yields a more distinct phenotype, clearly separated from M1, when compared to PM-G. We observed similar aging-related changes in the lipidome and cytokine profile of spleen, lung and liver tissue from mice. Hence, we hypothesize that during aging macrophage polarization towards M2 is impaired, which in turn drives chronic inflammation and disturbs tissue maintenance. By combining state-of-the art lipidomic and proteomic profiling we aim to uncover new molecular targets for pharmaceutical interventions to improve therapeutic strategies for elderly patients with chronic inflammatory diseases.

Project description:Respiratory syncytial virus (RSV) is the leading cause of severe lower respiratory tract infection in infants globally. Newborns, especially those born prematurely, are at increased risk of severe RSV-related illness, yet the influence of age on early-life airway epithelium innate immune responses remains relatively understudied. We established ex-vivo/in-vitro well-differentiated paediatric nasal epithelial cell (WD-PNEC) cultures derived from preterm and term infants at birth and again at one-year-old. Infection characteristics and innate immune responses were determined following in vitro RSV infection. RSV growth kinetics and cytopathology were similar irrespective of gestation or age. Secretion of interferon lambda-1 (IFN-λ1), CXCL10, CCL5, and CXCL8 were comparable between RSV-infected preterm- and term-newborn WD-PNECs. Importantly, following RSV infection, secretion of RSV-induced IFN-λ1 (p<0.05) and CCL5 (p<0.01) and expression of the IFN-stimulated gene, IFI6 (p<0.05) were significantly higher in one-year- compared to newborn-derived WD-PNECs. Interestingly, secretion of the cell signalling cytokine pleiotrophin increased significantly with longer gestation (p<0.01) and older age (p<0.001). Differential gene expression analysis demonstrated 156 differentially expressed genes (DEGs) with age and revealed transcriptomic changes linked to gestation in newborns that persisted at 1-year. These findings indicate two major conclusions. Firstly, we report transcriptomic differences in airway epithelial cell (AEC) development between term and preterm infants across the first year of life. Secondly, we demonstrate that RSV infection responses of AECs become more robust with age in early-life. Further investigation of identified DEGs and differentially expressed chemokines/cytokines is warranted to clarify their role in increased susceptibility of very young infants to severe RSV disease, as well as the significance of these factors in the emergence of wheezing phenotypes and long-term respiratory outcomes.

Dataset Information

Reduced inflammatory and Th1 transcriptional profiles in adult and geriatric cotton rats infected with respiratory syncytial virus

Dataset's files

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets