title: 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.affiliation: Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Tine
authors.initials: T
authors.lastname: Demoor
authors.forename: Bryan C
authors.initials: BC
authors.lastname: Petersen
authors.forename: Susan
authors.initials: S
authors.lastname: Morris
authors.forename: Sumanta
authors.initials: S
authors.lastname: Mukherjee
authors.forename: Catherine
authors.initials: C
authors.lastname: Ptaschinski
authors.forename: Denise E
authors.initials: DE
authors.lastname: De Almeida Nagata
authors.forename: Taro
authors.initials: T
authors.lastname: Kawai
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Ito
authors.forename: Shizuo
authors.initials: S
authors.lastname: Akira
authors.forename: Steven L
authors.initials: SL
authors.lastname: Kunkel
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Schaller
authors.forename: Nicholas W
authors.initials: NW
authors.lastname: Lukacs
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D000818:Animals; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000821:virology; D051379:Mice; D018345:Mice, Knockout; D018357:Respiratory Syncytial Virus Infections / Q000276:immunology* / Q000473:pathology / Q000821:virology*; D018113:Respiratory Syncytial Virus, Human / Q000276:immunology; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D019562:Viral Load / Q000235:genetics / Q000276:immunology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C512612:MAVS protein, mouse; C505371:MAVS protein, human