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

Abstract

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.

• Authors: Tine Demoor, Bryan C Petersen, Susan Morris, Sumanta Mukherjee, Catherine Ptaschinski, Denise E De Almeida Nagata, Taro Kawai, Toshihiro Ito, Shizuo Akira, Steven L Kunkel, Matthew A Schaller, Nicholas W Lukacs
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 189 Issue 12 Pg. 5942-53 (Dec 15 2012) ISSN: 1550-6606 [Electronic] United States
• PMID: 23136205 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Adaptor Proteins, Signal Transducing
• IPS-1 protein, mouse
• MAVS protein, human

Topics

• Adaptor Proteins, Signal Transducing (deficiency, genetics, physiology)
• Animals
• Humans
• Inflammation (genetics, immunology, virology)
• Mice
• Mice, Knockout
• Respiratory Syncytial Virus Infections (immunology, pathology, virology)
• Respiratory Syncytial Virus, Human (immunology)
• Signal Transduction (genetics, immunology)
• Viral Load (genetics, immunology)