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
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Cell Death / genetics
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Cell Death / immunology
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Cytotoxicity, Immunologic
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Disease Models, Animal
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Female
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Immunization, Passive
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Immunoglobulin G / metabolism*
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Immunoglobulin G / toxicity
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Influenza A virus / genetics
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Influenza A virus / immunology*
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Influenza Vaccines / genetics
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Influenza Vaccines / immunology*
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Influenza Vaccines / therapeutic use
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Lymphocyte Depletion / methods
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Macrophages, Alveolar / immunology*
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Macrophages, Alveolar / pathology
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Macrophages, Alveolar / virology
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Mice
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Mice, Inbred BALB C
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Mice, Inbred C57BL
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Mice, Knockout
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Orthomyxoviridae Infections / immunology
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Orthomyxoviridae Infections / pathology
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Orthomyxoviridae Infections / prevention & control*
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Protein Interaction Domains and Motifs / genetics
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Protein Interaction Domains and Motifs / immunology*
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Receptors, Fc / deficiency
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Receptors, Fc / physiology*
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Receptors, Fc / therapeutic use
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Receptors, IgG / deficiency
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Receptors, IgG / metabolism
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Receptors, IgG / physiology
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Viral Matrix Proteins / genetics
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Viral Matrix Proteins / immunology*
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Viral Matrix Proteins / therapeutic use
Substances
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Fcgr1 protein, mouse
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Fcgr3 protein, mouse
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Immunoglobulin G
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Influenza Vaccines
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M2 protein, Influenza A virus
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Receptors, Fc
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Receptors, IgG
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Viral Matrix Proteins