Immune responses to respiratory syncytial virus in neonate and adult mononuclear cells: Cytokine expression patterns and role of interferon regulatory factor -1.

摘要

RSV infections are ubiquitous in children but are most severe in infants in the first few months of life. Innate and adaptive immune responses were assessed to respiratory syncytial virus (RSV) in neonate mononuclear cells (MCs) obtained at birth (prior to any direct and independent exposure) and these responses were compared to those from adult MCs. Our hypothesis was that neonates exhibit innate and/or adaptive immune hyperresponsiveness to RSV. In neonate MCs, inactivated virus invoked large levels of the innate immune cytokines IL-6, TNF-alpha, and IL-10 and low levels of IFN-gamma and IL-12 but no adaptive immune cytokines. Live RSV induced lower levels (compared to inactivated virus) and fewer innate (IL-6, IL-10 and IFN-gamma) and no adaptive immune cytokines. In adult MCs, inactivated and live virus invoked cytokines reflecting both innate and adaptive immunity (IL-6, IFN-gamma, IL-2, TNF-alpha and IL-10). Further, NK cells (and not T cells) were the primary source of IFN-gamma in neonate MCs, whereas both NK cells and T cells contributed towards IFN-gamma in adult MCs to live RSV. RSV-induced proliferation in neonate MCs was not observed, though positive in adult MCs. Taken together, the results indicated that the immune response to live virus at birth was only innate in nature and could be characterized as hyporesponsive (compared to adults), thus contradicting our initial hypothesis. Immune suppression to live RSV in neonate MCs was found to be closely associated with dysregulation between type I (IFN-alpha) and type II (IFN-gamma) IFNs. IFN-alpha expression in neonate MCs was significantly more than in adult MCs to live RSV. Inhibition of the live RSV-induced IFN-alpha in neonate MCs led to significant increases in innate (IFN-gamma, IL-12, IL-18 and TNF-alpha) immune cytokine production. Interferon regulatory factor-1 (IRF-1) expression was part of the immune response to live RSV in adult MCs though not in neonate MCs and that the lack of IRF-1 upregulation in neonate MCs was reversed when IFN-alpha was neutralized. Overall, enhanced IFN-alpha expression suppressing innate immune cytokine production and IRF-1 expression in neonate MCs may account for the severity of early life RSV-induced illnesses.