TRAIL signaling is proinflammatory and proviral in a murine model of rhinovirus 1B infection

Abstract

the aim of this study is to elucidate the role of TRAIL during rhinovirus (RV) infection in vivo. Naïve wild-type and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-deficient (Tnfsf10) BALB/c mice were infected intranasally with RV1B. In separate experiments, Tnfsf10 mice were sensitized and challenged via the airway route with house dust mite (HDM) to induce allergic airways disease and then challenged with RVIB or UV-RVIB. Airway hyperreactivity (AHR) was invasively assessed as total airways resistance in response to increasing methacholine challenge and inflammation was assessed in bronchoalveolar lavage fluid at multiple time points postinfection. Chemokines were quantified by ELISA of whole lung lysates and viral load was determined by quantitative RT-PCR and tissue culture infective dose (TCID). Human airway epithelial cells (BEAS2B) were infected with RV1B and stimulated with recombinant TRAIL or neutralizing anti-TRAIL antibodies and viral titer assessed by TCID HDM-challenged Tnfsf10 mice were protected against RV-induced AHR and had suppressed cellular infiltration in the airways upon RV infection. Chemokine C-X-C-motif ligand 2 (CXCL2) production was suppressed in naïve Tnfsf10 mice infected with RV1B, with less RV1B detected 24 h postinfection. This was associated with reduced apoptotic cell death and a reduction of interferon (IFN)-λ2/3 but not IFN-α or IFN-β. TRAIL stimulation increased, whereas anti-TRAIL antibodies reduced viral replication in RV1B-infected BEAS2B cells in vitro. In conclusion, TRAIL promotes RV-induced AHR, inflammation and RV1B replication, implicating this molecule and its downstream signaling pathways as a possible target for the amelioration of RV1B-induced allergic and nonallergic lung inflammation and AHR.

Mechanisms and treatments for severe, steroid‐resistant allergic airway disease and asthma

“…TRAIL is an immune factor that regulates inflammation and apoptosis and has largely been studied in the context of tumor immunology. However, we, and others, have shown that TRAIL plays an important role in the pathogenesis of respiratory, and more recently gastrointestinal, tract disease. Significantly, we show that TRAIL plays an important role in early life Chlamydia infection‐induced severe AAD in later life .…”

In vivo experimental models of infection and disease

“…162 After observing increased levels of the TNF super family member protein, Tnfsf10 (TRAIL or CD253) production over a time course of RV-A1 infection in mice, Girkin et al compared RV-A1 infection in Tnfsf10 2/2 mice to wild-type BALB/c mice and observed an almost complete ablation of inflammatory responses to RV-A1. 163 Following RV infection, peribronchiolar inflammation and lung histopathology were reduced in Tnfsf10 2/2 mice; neutrophil and lymphocytes in BAL remained at baseline; and CD4 1 T cells, CD8 1 T cells, NKs, plasmacytoid dendritic cells (pDCs), and myeloid dendritic cells were all reduced in flow cytometry of total lung cells. 163 Tnfsf10 2/2 mice were protected from RV-induced AHR, and failed to develop RV-induced exacerbations of allergic airways disease.…”

“…163 Following RV infection, peribronchiolar inflammation and lung histopathology were reduced in Tnfsf10 2/2 mice; neutrophil and lymphocytes in BAL remained at baseline; and CD4 1 T cells, CD8 1 T cells, NKs, plasmacytoid dendritic cells (pDCs), and myeloid dendritic cells were all reduced in flow cytometry of total lung cells. 163 Tnfsf10 2/2 mice were protected from RV-induced AHR, and failed to develop RV-induced exacerbations of allergic airways disease. 163 An interesting proviral effect of TRAIL was also identified whereby Tnfsf10 2/2 mice had reduced viral load and anti-TRAIL antibodies reduced viral load (whereas recombinant TRAIL administration increased viral load) in BEAS2B cells infected with RV-A1 in vitro.…”

“…163 An interesting proviral effect of TRAIL was also identified whereby Tnfsf10 2/2 mice had reduced viral load and anti-TRAIL antibodies reduced viral load (whereas recombinant TRAIL administration increased viral load) in BEAS2B cells infected with RV-A1 in vitro. 163 This effect on viral load was independent of IFN responses and may be associated with an unidentified role of apoptosis in RV replication, which remains to be explored.…”

Aspiration techniques for bronchoalveolar lavage in translational respiratory research: Paving the way to develop novel therapeutic moieties

“…The main rationale and objective for collecting the BALf from widely used mice models of respiratory diseases is to evaluate differential cell counts, which is clinically significant in understanding and underpinning various process and mechanisms involved in inflammation, primarily at cellular level, but also in elucidating disease pathology at large [13][14][15][16][17]. This is an approach which also helps in obtaining a correlation between the BAL differential cell counts and various airway responsiveness parameters such as airway resistance, diffusing capacity of the lungs for carbon monoxide (DLCO) etc., which ultimately predicts the pathophysiological consequences occurring during various stages of the chronic inflammatory airway diseases.…”