title: Universal vaccine based on ectodomain of matrix protein 2 of influenza A: Fc receptors and alveolar macrophages mediate protection.
abstract: The ectodomain of matrix protein 2 (M2e) of influenza A virus is an attractive target for a universal influenza A vaccine: the M2e sequence is highly conserved across influenza virus subtypes, and induced humoral anti-M2e immunity protects against a lethal influenza virus challenge in animal models. Clinical phase I studies with M2e vaccine candidates have been completed. However, the in vivo mechanism of immune protection induced by M2e-carrier vaccination is unclear. Using passive immunization experiments in wild-type, FcRγ(-/-), FcγRI(-/-), FcγRIII(-/-), and (FcγRI, FcγRIII)(-/-) mice, we report in this study that Fc receptors are essential for anti-M2e IgG-mediated immune protection. M2e-specific IgG1 isotype Abs are shown to require functional FcγRIII for in vivo immune protection but other anti-M2e IgG isotypes can rescue FcγRIII(-/-) mice from a lethal challenge. Using a conditional cell depletion protocol, we also demonstrate that alveolar macrophages (AM) play a crucial role in humoral M2e-specific immune protection. Additionally, we show that adoptive transfer of wild-type AM into (FcγRI, FcγRIII)(-/-) mice restores protection by passively transferred anti-M2e IgG. We conclude that AM and Fc receptor-dependent elimination of influenza A virus-infected cells are essential for protection by anti-M2e IgG.
authors.affiliation: Department for Molecular Biomedical Research, Flanders Institute of Biotechnology (VIB), B-9052 Ghent, Belgium.
authors.forename: Karim
authors.initials: K
authors.lastname: El Bakkouri
authors.forename: Francis
authors.initials: F
authors.lastname: Descamps
authors.forename: Marina
authors.initials: M
authors.lastname: De Filette
authors.forename: Anouk
authors.initials: A
authors.lastname: Smet
authors.forename: Els
authors.initials: E
authors.lastname: Festjens
authors.forename: Ashley
authors.initials: A
authors.lastname: Birkett
authors.forename: Nico
authors.initials: N
authors.lastname: Van Rooijen
authors.forename: Sjef
authors.initials: S
authors.lastname: Verbeek
authors.forename: Walter
authors.initials: W
authors.lastname: Fiers
authors.forename: Xavier
authors.initials: X
authors.lastname: Saelens
mesh_terms: D000818:Animals; D016923:Cell Death / Q000235:genetics / Q000276:immunology; D003602:Cytotoxicity, Immunologic; D004195:Disease Models, Animal; D005260:Female; D007116:Immunization, Passive; D007074:Immunoglobulin G / Q000378:metabolism* / Q000633:toxicity; D009980:Influenza A virus / Q000235:genetics / Q000276:immunology*; D007252:Influenza Vaccines / Q000235:genetics / Q000276:immunology* / Q000627:therapeutic use; D008212:Lymphocyte Depletion / Q000379:methods; D016676:Macrophages, Alveolar / Q000276:immunology* / Q000473:pathology / Q000821:virology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009976:Orthomyxoviridae Infections / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D054730:Protein Interaction Domains and Motifs / Q000235:genetics / Q000276:immunology*; D011961:Receptors, Fc / Q000172:deficiency / Q000502:physiology* / Q000627:therapeutic use; D017452:Receptors, IgG / Q000172:deficiency / Q000378:metabolism / Q000502:physiology; D014763:Viral Matrix Proteins / Q000235:genetics / Q000276:immunology* / Q000627:therapeutic use; D000086082:Viroporin Proteins
chemical_list: D007074:Immunoglobulin G; D007252:Influenza Vaccines; D011961:Receptors, Fc; D017452:Receptors, IgG; D014763:Viral Matrix Proteins; C485701:Fcgr1 protein, mouse; C485700:Fcgr3 protein, mouse; C488937:M2 protein, Influenza A virus; D000086082:Viroporin Proteins