Host Transcription Profiles upon Primary Respiratory Syncytial Virus Infection

Abstract

Respiratory syncytial virus (RSV) is a common cause of severe lower respiratory tract infection in children.Severe RSV disease is related to an inappropriate immune response to RSV resulting in enhanced lung pathology which is influenced by host genetic factors. To gain insight into the early pathways of the pathogenesis of and immune response to RSV infection, we determined the transcription profiles of lungs and lymph nodes on days 1 and 3 after infection of mice. Primary RSV infection resulted in a rapid but transient innate, proinflammatory response, as exemplified by the induction of a large number of type I interferon-regulated genes and chemokine genes, genes involved in inflammation, and genes involved in antigen processing. Interestingly, this response is much stronger on day 1 than on day 3 after infection, indicating that the strong transcriptional response in the lung precedes the peak of viral replication. Surprisingly, the set of downregulated genes was small and none of these genes displayed strong down-regulation. Responses in the lung-draining lymph nodes were much less prominent than lung responses and are suggestive of NK cell activation. Our data indicate that at time points prior to the peak of viral replication and influx of inflammatory cells, the local lung response, measured at the transcriptional level, has already dampened down. The processes and pathways induced shortly after RSV infection can now be used for the selection of candidate genes for human genetic studies of children with severe RSV infection.The severity of respiratory syncytial virus (RSV) infection in young children varies from a nonclinical or mild upper respiratory tract infection to severe lower respiratory tract infection that may lead to hospitalization and occasionally to death. Some children are more prone to a severe course of disease, such as premature-born children, children younger than 3 months of age, children with chronic lung disease or congenital heart disease, and immunocompromised children (27,35). However, the biological mechanisms underlying the highly variable disease course in children are still poorly understood. The current belief is that children with severe RSV disease suffer from enhanced inflammatory lesions rather than from virus-induced cytopathology (25). In line with this, naturally occurring polymorphisms in genes affecting the inflammatory immune response influence the severity of RSV-induced disease (5,11,12,15).Immune responses to viral pathogens are initiated among others via the recognition of pathogen-associated molecular patterns by various Toll-like receptors (TLR), leading to the induction of innate immune responses, proinflammatory cytokines, and the Th1 pathway (reviewed in references 18 and 26). Innate immunity to RNA viruses is initiated by TLR3 and murine TLR7 or human TLR8, which are important for the responses to double-stranded and single-stranded RNAs, and through intracellular RNA recognition molecules, such as RIG-I and Mda5 (reviewed in reference 21). Both TLR3 and R...

RSV infection modulates IL-15 production and MICA levels in respiratory epithelial cells

“…In addition, because RSV infection induces a type 1 immune response characterised by increased IFN-c production [11], we determined how IFN-c alters RSVinduced IL-15 production and the levels of MHC class I and MICA molecules in epithelial cells.…”

Host response to mechanical ventilation for viral respiratory tract infection

“…In humans, severe RSV infection results in a predominantly neutrophil infiltrate in bronchoalveolar lavage fluid (BALF) [6] and a strong innate pro-inflammatory response, reflected by exhaustion of the peripheral blood neutrophil pool after peak values of viral load and disease severity [7]. In mice, the innate immune response is characterised by induction of type I interferon (IFN)-regulated genes and chemokine genes, and genes involved in inflammation and antigen processing [8].…”

“…In humans, severe RSV infection results in a predominantly neutrophil infiltrate in bronchoalveolar lavage fluid (BALF) [6] and a strong innate pro-inflammatory response, reflected by exhaustion of the peripheral blood neutrophil pool after peak values of viral load and disease severity [7]. In mice, the innate immune response is characterised by induction of type I interferon (IFN)-regulated genes and chemokine genes, and genes involved in inflammation and antigen processing [8].Although life-saving, mechanical ventilation may induce or aggravate pulmonary inflammation and lung injury. Ventilator-induced lung injury (VILI) results from relatively high tidal volumes (VT), causing alveolar and airway over distension, loss of surfactant and/or mechanical tissue damage [9,10].…”

TNF-α and Macrophages Are Critical for Respiratory Syncytial Virus–Induced Exacerbations in a Mouse Model of Allergic Airways Disease

“…RSV infection in animal models significantly increases neutrophil, eosinophil, and lymphocyte infiltration into the airways and induces high levels of proinflammatory cytokines including IL-1, IL-6, IL-12, IL-13, IFN-g, TNF-a, MCP 1 (MCP-1/CCL2), CCL3 (MIP-1a), CCL5 (RANTES), CXCL10 (IP-10), and keratinocyte-derived protein chemokine (KC/CXCL1; the mouse homolog of IL-8) (19)(20)(21)(22). The specific patterns of cytokine induction (and their impact on AHR) varies depending on the RSV strain being assessed.…”