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 produced as both membrane-anchored and secreted forms by infected cells. Immunization with secreted RSV G (Gs) or formalin-inactivated alumprecipitated RSV (FI-RSV) predisposes mice to immune responses involving a Th2 cell phenotype which results in more severe illness and pathology, decreased viral clearance, and increased pulmonary eosinophilia upon subsequent RSV challenge. These responses are associated with increased interleukin-4 (IL-4) production in FI-RSV-primed mice, and the responses are IL-4 dependent. RNase protection assays demonstrated that similar levels of IL-4 mRNA were induced after RSV challenge in mice primed with vaccinia virus expressing Gs (vvGs) or 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 neutralizing anti-IL-4 antibody 11.B11 during vaccinia virus priming did not alter the levels of vvGs-induced IL-5, IL-13, pulmonary eosinophilia, illness, or RSV titers upon RSV challenge, although immunoglobulin G (IgG) isotype profiles revealed that more IgG2a was produced. vvGs-priming of IL-4-deficient mice demonstrated that G-induced airway eosinophilia was not dependent on IL-4. In contrast, airway eosinophilia induced by FI-RSV priming was significantly 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 mice by an IL-4-independent mechanism.
Johnson
T R
TR
Departments of Microbiology & Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-2582, USA.
Graham
B S
BS
D000818:Animals; D000956:Antigens, Viral / Q000276:immunology; D004802:Eosinophilia / Q000276:immunology / Q000821:virology*; D015707:HN Protein; D018793:Interleukin-13 / Q000097:blood / Q000276:immunology*; D015847:Interleukin-4 / Q000276:immunology*; D015848:Interleukin-5 / Q000097:blood / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D018357:Respiratory Syncytial Virus Infections / Q000097:blood / Q000276:immunology*; D012136:Respiratory Syncytial Viruses; D014759:Viral Envelope Proteins / Q000276:immunology; D014764:Viral Proteins / Q000276:immunology*
D000956:Antigens, Viral; D015707:HN Protein; D018793:Interleukin-13; D015848:Interleukin-5; D014759:Viral Envelope Proteins; D014764:Viral Proteins; C116204:attachment protein G; D015847:Interleukin-4