Contribution of Fc gamma 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 Fc gamma receptors (Fc gamma Rs) expressed on the surface of DCs. Remarkably, we also observed that in the absence of hRSV-specific antibodies Fc gamma RIII 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 Fc gamma Rs can contribute significantly to the modulation of DC function by hRSV and hRSV-IC. Further, we provide evidence for an involvement of Fc gamma RIII in the development of hRSV pathogenesis. Keywords. Author Keywords:dendritic cells; Fc gamma receptors; human respiratory syncytial virus; immune complexes; neutralizing antibodies; palivizumab . KeyWords Plus:NEUTRALIZING MONOCLONAL-ANTIBODIES; ENTERICA SEROVAR ENTERITIDIS; ANTIGEN PRESENTATION; IMMUNE-COMPLEX; FUSION PROTEIN; DEPENDENT ENHANCEMENT; PRETERM INFANTS; INFLUENZA-VIRUS; RSV INFECTION; RISK-FACTORS