TRAIL signaling is proinflammatory and proviral in a murine model of rhinovirus 1B infection.
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 (TCID50). Human airway epithelial cells (BEAS2B) were infected with RV1B and stimulated with recombinant TRAIL or neutralizing anti-TRAIL antibodies and viral titer assessed by TCID50HDM-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.
Experimental and Translational Respiratory Medicine Group, University of Newcastle and Hunter Medical Research Institute, Newcastle, Australia.|Priority Research Centre for Healthy Lungs, University of Newcastle and Hunter Medical Research Institute, Newcastle, Australia.
Jason L
0000-0002-0739-1070
JL
Girkin
Experimental and Translational Respiratory Medicine Group, University of Newcastle and Hunter Medical Research Institute, Newcastle, Australia.|Priority Research Centre GrowUpWell, University of Newcastle and Hunter Medical Research Institute, Newcastle, Australia.
Luke M
LM
Hatchwell
Experimental and Translational Respiratory Medicine Group, University of Newcastle and Hunter Medical Research Institute, Newcastle, Australia.|Priority Research Centre GrowUpWell, University of Newcastle and Hunter Medical Research Institute, Newcastle, Australia.
Adam M
AM
Collison
Priority Research Centre for Healthy Lungs, University of Newcastle and Hunter Medical Research Institute, Newcastle, Australia.|Priority Research Centre GrowUpWell, University of Newcastle and Hunter Medical Research Institute, Newcastle, Australia.|Microbiology, Asthma, and Airways Research Group, University of Newcastle and Hunter Medical Research Institute, Newcastle, Australia.
Malcolm R
MR
Starkey
Priority Research Centre for Healthy Lungs, University of Newcastle and Hunter Medical Research Institute, Newcastle, Australia.|Microbiology, Asthma, and Airways Research Group, University of Newcastle and Hunter Medical Research Institute, Newcastle, Australia.
Philip M
PM
Hansbro
Department of Immunology, Juntendo University, School of Medicine, Tokyo, Japan; and.
Hideo
H
Yagita
Priority Research Centre for Healthy Lungs, University of Newcastle and Hunter Medical Research Institute, Newcastle, Australia.
Paul S
PS
Foster
Experimental and Translational Respiratory Medicine Group, University of Newcastle and Hunter Medical Research Institute, Newcastle, Australia; Joerg.Mattes@newcastle.edu.au.|Priority Research Centre GrowUpWell, University of Newcastle and Hunter Medical Research Institute, Newcastle, Australia.|Paediatric Respiratory and Sleep Medicine Unit, John Hunter Children's Hospital, Newcastle, Australia.
Joerg
J
Mattes
D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology; D016535:Bronchial Hyperreactivity / Q000473:pathology; D003713:Dendritic Cells / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D006967:Hypersensitivity / Q000378:metabolism / Q000469:parasitology / Q000473:pathology; D007249:Inflammation / Q000473:pathology* / Q000821:virology*; D018836:Inflammation Mediators / Q000378:metabolism; D007370:Interferon Type I / Q000378:metabolism; D007694:Killer Cells, Natural / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008807:Mice, Inbred BALB C; D010749:Phosphoprotein Phosphatases / Q000378:metabolism; D010850:Picornaviridae Infections / Q000276:immunology* / Q000473:pathology* / Q000821:virology*; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D039981:Pyroglyphidae / Q000187:drug effects / Q000502:physiology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012229:Rhinovirus / Q000187:drug effects / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000172:deficiency / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases; D014779:Virus Replication / Q000187:drug effects
D000998:Antiviral Agents; D018836:Inflammation Mediators; D007370:Interferon Type I; D011506:Proteins; D012333:RNA, Messenger; D053221:TNF-Related Apoptosis-Inducing Ligand; C109037:Mid1 protein, mouse; D044767:Ubiquitin-Protein Ligases; D010749:Phosphoprotein Phosphatases
TRAIL; asthma; inflammation; rhinovirus; tumor necrosis factor-related apoptosis-inducing ligand