title: Plasmacytoid dendritic cells promote host defense against acute pneumovirus infection via the TLR7-MyD88-dependent signaling pathway.
abstract: Human respiratory syncytial virus (RSV) is the leading cause of lower respiratory tract infection in infants. In human infants, plasmacytoid dendritic cells (pDC) are recruited to the nasal compartment during infection and initiate host defense through the secretion of type I IFN, IL-12, and IL-6. However, RSV-infected pDC are refractory to TLR7-mediated activation. In this study, we used the rodent-specific pathogen, pneumonia virus of mice (PVM), to determine the contribution of pDC and TLR7 signaling to the development of the innate inflammatory and early adaptive immune response. In wild-type, but not TLR7- or MyD88-deficient mice, PVM inoculation led to a marked infiltration of pDC and increased expression of type I, II, and III IFNs. The delayed induction of IFNs in the absence of TLR7 or MyD88 was associated with a diminished innate inflammatory response and augmented virus recovery from lung tissue. In the absence of TLR7, PVM-specific CD8(+) T cell cytokine production was abrogated. The adoptive transfer of TLR7-sufficient, but not TLR7-deficient pDC to TLR7 gene-deleted mice recapitulated the antiviral responses observed in wild-type mice and promoted virus clearance. In summary, TLR7-mediated signaling by pDC is required for appropriate innate responses to acute pneumovirus infection. It is conceivable that as-yet-unidentified defects in the TLR7 signaling pathway may be associated with elevated levels of RSV-associated morbidity and mortality among otherwise healthy human infants.
authors.affiliation: Centre for Asthma and Respiratory Diseases, University of Newcastle, New South Wales 2300, Australia.
authors.forename: Sophia
authors.initials: S
authors.lastname: Davidson
authors.forename: Gerard
authors.initials: G
authors.lastname: Kaiko
authors.forename: Zhixuan
authors.initials: Z
authors.lastname: Loh
authors.forename: Amit
authors.initials: A
authors.lastname: Lalwani
authors.forename: Vivian
authors.initials: V
authors.lastname: Zhang
authors.forename: Kirsten
authors.initials: K
authors.lastname: Spann
authors.forename: Shen Yun
authors.initials: SY
authors.lastname: Foo
authors.forename: Nicole
authors.initials: N
authors.lastname: Hansbro
authors.forename: Satoshi
authors.initials: S
authors.lastname: Uematsu
authors.forename: Shizuo
authors.initials: S
authors.lastname: Akira
authors.forename: Klaus I
authors.initials: KI
authors.lastname: Matthaei
authors.forename: Helene F
authors.initials: HF
authors.lastname: Rosenberg
authors.forename: Paul S
authors.initials: PS
authors.lastname: Foster
authors.forename: Simon
authors.initials: S
authors.lastname: Phipps
mesh_terms: D056704:Adaptive Immunity; D019264:Adoptive Transfer; D000818:Animals; D003713:Dendritic Cells / Q000276:immunology*; D007372:Interferons / Q000235:genetics / Q000276:immunology; D008562:Membrane Glycoproteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D029122:Murine pneumonia virus / Q000276:immunology*; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000378:metabolism*; D018186:Pneumovirus Infections / Q000276:immunology*; D015398:Signal Transduction; D051199:Toll-Like Receptor 7 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*
chemical_list: D008562:Membrane Glycoproteins; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; C477038:Tlr7 protein, mouse; D051199:Toll-Like Receptor 7; D007372:Interferons