RESUMEN
Respiratory syncytial virus (RSV) is a major cause of respiratory morbidity, resulting in hospitalization for bronchiolitis in some infected infants that is associated with wheeze in later life. Genetic factors are known to affect the severity of the sequelae after RSV infection, but the complexity of the temporal and genetic effects makes it difficult to analyze this response in studies in man. Therefore, we developed a murine genetic model to analyze the sequelae occurring after RSV infection in early life. Haplotype-based genetic analysis of interstrain differences in severity identified the MHC as an important genetic determinant. This was confirmed by analysis of responses in congenic mice with different MHC haplotypes. We also found that susceptible strains had high CD8 levels during secondary infection. Analysis of first filial generation, second filial generation, and back-cross progeny produced by intercrossing resistant (H-2(k), C3H/HeN) and sensitive (H-2(b), BALB/c) strains indicated that susceptibility to sequelae after RSV infection was dominantly inherited but also segregated in a non-MHC-dependent manner. Thus, MHC haplotype and its effect on CD8 cell response is an important determinant of the outcome of neonatal RSV infection.
Asunto(s)
Predisposición Genética a la Enfermedad/genética , Complejo Mayor de Histocompatibilidad/genética , Infecciones por Virus Sincitial Respiratorio/genética , Animales , Animales Congénicos , Animales Recién Nacidos/inmunología , Asma/virología , Separación Celular , Mapeo Cromosómico , Modelos Animales de Enfermedad , Citometría de Flujo , Haplotipos , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Polimorfismo de Nucleótido Simple , Ruidos Respiratorios/etiología , Infecciones por Virus Sincitial Respiratorio/complicaciones , Virus Sincitiales RespiratoriosRESUMEN
A conserved fragment comprising amino acid residues 130-230 of the G glycoprotein of human respiratory syncytial virus subtype A was expressed in the commensal bacterium Streptococcus gordonii. Recombinant streptococci displaying the G domain at the cell surface were used to immunize mice via both parenteral and mucosal routes. Subcutaneous immunization induced respiratory syncytial virus-specific serum immunoglobin G (IgG) capable of partially controlling virus replication in the lungs. Intranasal immunization with live bacteria stimulated the production of IgA against both the whole virus and the G domain in serum and bronchoalveolar fluid. Upon challenge, immunized animals had significantly lower virus titres in the lungs than the controls. Our results show for the first time that the G domain-expressing S. gordonii strain elicits both systemic and mucosal immunity that reduced respiratory syncytial virus replication in the lungs of mice.