IPS-1 signaling has a nonredundant role in mediating antiviral responses and the clearance of respiratory syncytial virus

The cytosolic RNA helicases melanoma differentiation-associated gene 5 and retinoic acid-inducible gene-I and their adaptor IFN-β promoter stimulator (IPS-1) have been implicated in the recognition of viral RNA and the production of type I IFN. Complementing the endosomal TLR, melanoma differentiati...

Full description

Saved in:
Bibliographic Details
Published in:The Journal of immunology (1950) 2012-12, Vol.189 (12), p.5942-5953
Main Authors: Demoor, Tine, Petersen, Bryan C, Morris, Susan, Mukherjee, Sumanta, Ptaschinski, Catherine, De Almeida Nagata, Denise E, Kawai, Taro, Ito, Toshihiro, Akira, Shizuo, Kunkel, Steven L, Schaller, Matthew A, Lukacs, Nicholas W
Format: Article
Language:English
Subjects:
Adaptor Proteins, Signal Transducing - deficiency
Adaptor Proteins, Signal Transducing - genetics
Adaptor Proteins, Signal Transducing - physiology
Animals
Humans
Inflammation - genetics
Inflammation - immunology
Inflammation - virology
Mice
Mice, Knockout
Respiratory syncytial virus
Respiratory Syncytial Virus Infections - immunology
Respiratory Syncytial Virus Infections - pathology
Respiratory Syncytial Virus Infections - virology
Respiratory Syncytial Virus, Human - immunology
Signal Transduction - genetics
Signal Transduction - immunology
Viral Load - genetics
Viral Load - immunology
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:The cytosolic RNA helicases melanoma differentiation-associated gene 5 and retinoic acid-inducible gene-I and their adaptor IFN-β promoter stimulator (IPS-1) have been implicated in the recognition of viral RNA and the production of type I IFN. Complementing the endosomal TLR, melanoma differentiation-associated gene 5, and retinoic acid-inducible gene-I provides alternative mechanisms for viral detection in cells with reduced phagocytosis or autophagy. The infection route of respiratory syncytial virus (RSV)-via fusion of virus particles with the cell membrane-points to IPS-1 signaling as the pathway of choice for downstream antiviral responses. In the current study, viral clearance and inflammation resolution were indeed strongly affected by the absence of an initial IPS-1-mediated IFN-β response. Despite the blunted inflammatory response in IPS-1-deficient alveolar epithelial cells, pulmonary macrophages, and CD11b(+) dendritic cells (DC), the lungs of RSV-infected IPS-1-knockout mice showed augmented recruitment of inflammatory neutrophils, monocytes, and DC. Interestingly, pulmonary CD103(+) DC could functionally compensate for IPS-1 deficiency with the upregulation of certain inflammatory cytokines and chemokines, possibly via TLR3 and TLR7 signaling. The increased inflammation and reduced viral clearance in IPS-1-knockout mice was accompanied by increased T cell activation and IFN-γ production. Experiments with bone marrow chimeras indicated that RSV-induced lung pathology was most severe when IPS-1 expression was lacking in both immune and nonimmune cell populations. Similarly, viral clearance was rescued upon restored IPS-1 signaling in either the nonimmune or the immune compartment. These data support a nonredundant function for IPS-1 in controlling RSV-induced inflammation and viral replication.
ISSN:0022-1767
1550-6606
DOI:10.4049/jimmunol.1201763