IFN-γ immune priming of macrophages in vivo induces prolonged STAT1 binding and protection against Cryptococcus neoformans

Development of vaccines against opportunistic infections is difficult as patients most at risk of developing disease are deficient in aspects of the adaptive immune system. Here, we utilized an experimental immunization strategy to induce innate memory in macrophages in vivo. Unlike current trained...

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Bibliographic Details
Published in:PLoS pathogens 2018-10, Vol.14 (10), p.e1007358-e1007358
Main Authors: Leopold Wager, Chrissy M, Hole, Camaron R, Campuzano, Althea, Castro-Lopez, Natalia, Cai, Hong, Caballero Van Dyke, Marley C, Wozniak, Karen L, Wang, Yufeng, Wormley, Jr, Floyd L
Format: Article
Language:English
Subjects:
Acetylation
Acquired immune deficiency syndrome
Adaptive systems
AIDS
Antigens
Binding
Biology
Biology and Life Sciences
Cytokines
DNA methylation
Epigenetics
Fungal infections
Fungicides
Genes
Health risks
HIV
Human immunodeficiency virus
Immune response
Immune system
Immunity
Immunization
Immunological memory
Immunology
Infectious diseases
Lymphocytes
Macrophages
Medicine and Health Sciences
Pathogens
Phenotypes
Priming
Research and Analysis Methods
Ribonucleic acid
RNA
Stat1 protein
Vaccines
γ-Interferon
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Summary:Development of vaccines against opportunistic infections is difficult as patients most at risk of developing disease are deficient in aspects of the adaptive immune system. Here, we utilized an experimental immunization strategy to induce innate memory in macrophages in vivo. Unlike current trained immunity models, we present an innate memory-like phenotype in macrophages that is maintained for at least 70 days post-immunization and results in complete protection against secondary challenge in the absence of adaptive immune cells. RNA-seq analysis of in vivo IFN-γ primed macrophages revealed a rapid up-regulation of IFN-γ and STAT1 signaling pathways following secondary challenge. The enhanced cytokine recall responses appeared to be pathogen-specific, dependent on changes in histone methylation and acetylation, and correlated with increased STAT1 binding to promoter regions of genes associated with protective anti-fungal immunity. Thus, we demonstrate an alternative mechanism to induce macrophage innate memory in vivo that facilitates pathogen-specific vaccine-mediated immune responses.
ISSN:1553-7374
1553-7366
1553-7374
DOI:10.1371/journal.ppat.1007358