Universal vaccine based on ectodomain of matrix protein 2 of influenza A: Fc receptors and alveolar macrophages mediate protection

J Immunol. 2011 Jan 15;186(2):1022-31. doi: 10.4049/jimmunol.0902147. Epub 2010 Dec 17.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Death / genetics
  • Cell Death / immunology
  • Cytotoxicity, Immunologic
  • Disease Models, Animal
  • Female
  • Immunization, Passive
  • Immunoglobulin G / metabolism*
  • Immunoglobulin G / toxicity
  • Influenza A virus / genetics
  • Influenza A virus / immunology*
  • Influenza Vaccines / genetics
  • Influenza Vaccines / immunology*
  • Influenza Vaccines / therapeutic use
  • Lymphocyte Depletion / methods
  • Macrophages, Alveolar / immunology*
  • Macrophages, Alveolar / pathology
  • Macrophages, Alveolar / virology
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Orthomyxoviridae Infections / immunology
  • Orthomyxoviridae Infections / pathology
  • Orthomyxoviridae Infections / prevention & control*
  • Protein Interaction Domains and Motifs / genetics
  • Protein Interaction Domains and Motifs / immunology*
  • Receptors, Fc / deficiency
  • Receptors, Fc / physiology*
  • Receptors, Fc / therapeutic use
  • Receptors, IgG / deficiency
  • Receptors, IgG / metabolism
  • Receptors, IgG / physiology
  • Viral Matrix Proteins / genetics
  • Viral Matrix Proteins / immunology*
  • Viral Matrix Proteins / therapeutic use

Substances

  • Fcgr1 protein, mouse
  • Fcgr3 protein, mouse
  • Immunoglobulin G
  • Influenza Vaccines
  • M2 protein, Influenza A virus
  • Receptors, Fc
  • Receptors, IgG
  • Viral Matrix Proteins