A systems-based approach to analyse the host response in murine lung macrophages challenged with respiratory syncytial virus

Abstract

BackgroundRespiratory syncytial virus (RSV) is an important cause of lower respiratory tract infection in young children. The degree of disease severity is determined by the host response to infection. Lung macrophages play an important early role in the host response to infection and we have used a systems-based approach to examine the host response in RSV-infected lung-derived macrophage cells.ResultsLung macrophage cells could be efficiently infected (>95%) with RSV in vitro, and the expression of several virus structural proteins could be detected. Although we failed to detect significant levels of virus particle production, virus antigen could be detected up until 96 hours post-infection (hpi). Microarray analysis indicated that 20,086 annotated genes were expressed in the macrophage cells, and RSV infection induced an 8.9% and 11.3% change in the global gene transcriptome at 4 hpi and 24 hpi respectively. Genes showing up-regulated expression were more numerous and exhibited higher changes in expression compared to genes showing down-regulated expression. Based on gene ontology, genes with cytokine, antiviral, cell death, and signal transduction functions showed the highest increases in expression, while signalling transduction, RNA binding and protein kinase genes showed the greatest reduction in expression levels. Analysis of the global gene expression profile using pathway enrichment analysis confirmed that up-regulated expression of pathways related to pathogen recognition, interferon signalling and antigen presentation occurred in the lung macrophage cells challenged with RSV.ConclusionOur data provided a comprehensive analysis of RSV-induced gene expression changes in lung macrophages. Although virus gene expression was detected, our data was consistent with an abortive infection and this correlated with the activation of several antivirus signalling pathways such as interferon type I signalling and cell death signalling. RSV infection induced a relatively large increase in pro-inflammatory cytokine expression, however the maintenance of this pro-inflammatory response was not dependent on the production of infectious virus particles. The sustained pro-inflammatory response even in the absence of a productive infection suggests that drugs that control the pro-inflammatory response may be useful in the treatment of patients with severe RSV infection.

Systems-based approach to examine the cytokine responses in primary mouse lung macrophages infected with low pathogenic avian Influenza virus circulating in South East Asia

“…Interestingly, H5N3 virus-infected PMФ cells induce expression patterns and pathways (including cytokines) that are similar to the response that we have observed in RSV-infected PMФ cells (Additional file 1: Figure S1C, D; Additional file 2) [32]. RSV is another important virus that can cause lung tissue damage via pro-inflammatory cytokine induction in the lower airway.…”

Impact of Interferon Lambda 4 Genotype on Interferon‐Stimulated Gene Expression During Direct‐Acting Antiviral Therapy for Hepatitis C

“…Modeling of the dynamics of HCV under therapy indicates that destruction of persistently infected cells could play a role in long‐term clearance . Our findings may be relevant to this idea given that activation of ISGs can be linked to induction of cell death mechanisms . This is evident from our own data, which indicate cell death pathway up‐regulation both using in vitro IFNα and in the DAA trial (Supporting Table ).…”

Failure of Respiratory Defenses in the Pathogenesis of Bacterial Pneumonia of Cattle

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