An attenuated innate immune response to a clinical strain of respiratory syncytial virus (RSV) in human monocyte derived dendritic cells (MDDC) (37.43)

Abstract

Abstract RSV clinical strain 19 was isolated from a severely affected infant and was characterized in a model in which mice develop severe disease defined by enhanced mucous secretion, IL-13 expression, and low expression of IFN-α compared to infection with the lab strain A2. We compared the innate response induced by RSV strain 19 with strain A2 in human MDDC using a qRT-PCR based array and a novel qRT-PCR assay we developed that discriminates among all IFN-α and IFN-λ subtypes and also includes IFN-β. Human MDDC expressed a similar profile of inflammatory and IFN response genes (IRG) to both RSV strains. The response to strain 19, however, was attenuated for many IRG and inflammatory genes, including CXCL9, CXCL10, CCL2 and genes associated with the RIG-I pathway. Similarly, MDDC expressed IFN-α1, IFN-β, IFN-λ1, and -λ2 in response to either strain, but strain 19 expressed lower levels of each. Another IFN subtype, IFN-α14, was expressed by 5 donors in response to strain A2 but was undetectable in response to strain 19. IFN-α protein, however, was undetectable in 9 of 10 supernatants from strain 19 in contrast to 1 of 10 supernatants from A2 infected cells. Evasion or active suppression of the IFN-α, -β or -λ response may explain the enhanced pathogenicity of strain 19. The qualitative difference in IFN-α14 expression in response to A2 but not 19 suggests a potentially important role for this subtype.