Secreted respiratory syncytial virus G glycoprotein induces interleukin-5 (IL-5), IL-13, and eosinophilia by an IL-4-independent mechanism

The attachment glycoprotein G of respiratory syncytial virus (RSV) is produ ced as both membrane-anchored and secreted forms by infected cells. Immuniz ation with secreted RSV G (Gs) or formalin-inactivated alum-precipitated RS V (FI-RSV) predisposes mice to immune responses involving a Th2 cell phenot ype which results in more severe illness and pathology, decreased viral cle arance, and increased pulmonary eosinophilia upon subsequent RSV challenge. These responses are associated with increased interleukin-4 (IL-4) product ion in FI-RSV-primed mice, and the responses are IL-4 dependent. RNase prot ection assays demonstrated that similar levels of IL-4 mRNA were induced af ter RSV challenge in mice primed with vaccinia virus expressing Gs (vvGs) o r a construct expressing only membrane-anchored G (vvGr). However, upon RSV challenge, vvGs-primed mice produced significantly greater levels of IL-5 and IL-13 mRNA and protein than vvGr-primed mice. Administration of neutral izing anti-IL-l antibody 11.B11 during vaccinia virus priming did not alter the levels of vvGs-induced IL-5, IL-13, pulmonary eosinophilia, illness, o r RSV titers upon RSV challenge, although immunoglobulin G (IgG) isotype pr ofiles revealed that more IgG2a was produced. vvGs-priming of IL-4-deficien t mice demonstrated that G-induced airway eosinophilia was not dependent on IL-4. In contrast, airway eosinophilia induced by FI-RSV priming was signi ficantly reduced in IL-4-deficient mice. Thus we conclude that, in contrast to FI-RSV, the secreted form of RSV G can directly induce IL-5 and IL-13, producing pulmonary eosinophilia and enhanced illness in RSV-challenged mic e by an IL-4-independent mechanism.