Plant-derived virus-like particle vaccines drive cross-presentation of influenza A hemagglutinin peptides by human monocyte-derived macrophages

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作者
Alexander I. Makarkov
Makan Golizeh
Elizabeth Ruiz-Lancheros
Angelica A. Gopal
Ian N. Costas-Cancelas
Sabrina Chierzi
Stephane Pillet
Nathalie Charland
Nathalie Landry
Isabelle Rouiller
Paul W. Wiseman
Momar Ndao
Brian J. Ward
机构
[1] McGill University,Division of Experimental Medicine, Department of Medicine
[2] Research Institute of McGill University Health Centre,Infectious Diseases and Immunity in Global Health Program
[3] McGill University,Department of Chemistry
[4] McGill University,Department of Physiology
[5] McGill University,Department of Anatomy & Cell Biology, Faculty of Medicine, Groupe de Recherche Axé sur la Structure des Protéines (GRASP), Groupe d’Étude des Protéines Membranaires (GEPROM)
[6] Montreal General Hospital,Research Institute of McGill University Health Centre
[7] Medicago Inc.,Department of Biochemistry and Molecular Biology and Bio21 Molecular Science and Biotechnology Institute
[8] The University of Melbourne,Department of Physics
[9] McGill University,Department of Medicine, Division of Infectious Diseases, Faculty of Medicine
[10] McGill University,undefined
[11] Medicago Inc.,undefined
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npj Vaccines | / 4卷
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摘要
A growing body of evidence supports the importance of T cell responses to protect against severe influenza, promote viral clearance, and ensure long-term immunity. Plant-derived virus-like particle (VLP) vaccines bearing influenza hemagglutinin (HA) have been shown to elicit strong humoral and CD4+ T cell responses in both pre-clinical and clinical studies. To better understand the immunogenicity of these vaccines, we tracked the intracellular fate of a model HA (A/California/07/2009 H1N1) in human monocyte-derived macrophages (MDMs) following delivery either as VLPs (H1-VLP) or in soluble form. Compared to exposure to soluble HA, pulsing with VLPs resulted in ~3-fold greater intracellular accumulation of HA at 15 min that was driven by clathrin-mediated and clathrin-independent endocytosis as well as macropinocytosis/phagocytosis. At 45 min, soluble HA had largely disappeared suggesting its handling primarily by high-degradative endosomal pathways. Although the overall fluorescence intensity/cell had declined 25% at 45 min after H1-VLP exposure, the endosomal distribution pattern and degree of aggregation suggested that HA delivered by VLP had entered both high-degradative late and low-degradative static early and/or recycling endosomal pathways. At 45 min in the cells pulsed with VLPs, HA was strongly co-localized with Rab5, Rab7, Rab11, MHC II, and MHC I. High-resolution tandem mass spectrometry identified 115 HA-derived peptides associated with MHC I in the H1-VLP-treated MDMs. These data suggest that HA delivery to antigen-presenting cells on plant-derived VLPs facilitates antigen uptake, endosomal processing, and cross-presentation. These observations may help to explain the broad and cross-reactive immune responses generated by these vaccines.
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