title: Contribution of Fcγ receptors to human respiratory syncytial virus pathogenesis and the impairment of T-cell activation by dendritic cells.
abstract: Human respiratory syncytial virus (hRSV) is the leading cause of infant hospitalization related to respiratory disease. Infection with hRSV produces abundant infiltration of immune cells into the airways, which combined with an exacerbated pro-inflammatory immune response can lead to significant damage to the lungs. Human RSV re-infection is extremely frequent, suggesting that this virus may have evolved molecular mechanisms that interfere with host adaptive immunity. Infection with hRSV can be reduced by administering a humanized neutralizing antibody against the virus fusion protein in high-risk infants. Although neutralizing antibodies against hRSV effectively block the infection of airway epithelial cells, here we show that both, bone marrow-derived dendritic cells (DCs) and lung DCs undergo infection with IgG-coated virus (hRSV-IC), albeit abortive. Yet, this is enough to negatively modulate DC function. We observed that such a process is mediated by Fcγ receptors (FcγRs) expressed on the surface of DCs. Remarkably, we also observed that in the absence of hRSV-specific antibodies FcγRIII knockout mice displayed significantly less cellular infiltration in the lungs after hRSV infection, compared with wild-type mice, suggesting a potentially harmful, IgG-independent role for this receptor in hRSV disease. Our findings support the notion that FcγRs can contribute significantly to the modulation of DC function by hRSV and hRSV-IC. Further, we provide evidence for an involvement of FcγRIII in the development of hRSV pathogenesis.
authors.affiliation: Millennium Institute on Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago de Chile, Chile.
authors.forename: Roberto S
authors.initials: RS
authors.lastname: Gómez
authors.affiliation: Millennium Institute on Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago de Chile, Chile.
authors.forename: Bruno A
authors.initials: BA
authors.lastname: Ramirez
authors.affiliation: Millennium Institute on Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago de Chile, Chile.
authors.forename: Pablo F
authors.initials: PF
authors.lastname: Céspedes
authors.affiliation: Millennium Institute on Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago de Chile, Chile.
authors.forename: Kelly M
authors.initials: KM
authors.lastname: Cautivo
authors.affiliation: Millennium Institute on Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago de Chile, Chile.|INSERM U1064, Nantes, France.
authors.forename: Sebastián A
authors.initials: SA
authors.lastname: Riquelme
authors.affiliation: Millennium Institute on Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago de Chile, Chile.
authors.forename: Carolina E
authors.initials: CE
authors.lastname: Prado
authors.affiliation: Millennium Institute on Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago de Chile, Chile.
authors.forename: Pablo A
authors.initials: PA
authors.lastname: González
authors.affiliation: Millennium Institute on Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago de Chile, Chile.|INSERM U1064, Nantes, France.|Departamento de Reumatología, Facultad de Medicina. Pontificia Universidad Católica de Chile, Santiago de Chile, Chile.
authors.forename: Alexis M
authors.initials: AM
authors.lastname: Kalergis
mesh_terms: D056704:Adaptive Immunity; D000818:Animals; D057134:Antibodies, Neutralizing / Q000494:pharmacology; D000914:Antibodies, Viral / Q000276:immunology / Q000378:metabolism; D000998:Antiviral Agents / Q000494:pharmacology; D002478:Cells, Cultured; D018920:Coculture Techniques; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism* / Q000821:virology; D004195:Disease Models, Animal; D007074:Immunoglobulin G / Q000276:immunology / Q000378:metabolism; D008168:Lung / Q000187:drug effects / Q000276:immunology / Q000378:metabolism* / Q000821:virology; D008213:Lymphocyte Activation / Q000187:drug effects; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000069455:Palivizumab / Q000494:pharmacology; D017452:Receptors, IgG / Q000172:deficiency / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D018357:Respiratory Syncytial Virus Infections / Q000188:drug therapy / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000821:virology; D018113:Respiratory Syncytial Virus, Human / Q000187:drug effects / Q000276:immunology / Q000472:pathogenicity*; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism* / Q000821:virology; D019562:Viral Load; D014779:Virus Replication
chemical_list: D057134:Antibodies, Neutralizing; D000914:Antibodies, Viral; D000998:Antiviral Agents; D016207:Cytokines; C499172:Fcgr2b protein, mouse; C485700:Fcgr3 protein, mouse; D007074:Immunoglobulin G; D017452:Receptors, IgG; D000069455:Palivizumab
keywords: Fcγ receptors; dendritic cells; human respiratory syncytial virus; immune complexes; neutralizing antibodies; palivizumab