IFN-γ–induced trained immunity enhances killing of priority pathogens in healthy and genetically vulnerable individuals
Dearbhla M. Murphy, Isabella Batten, Aoife O’Farrell, Simon R. Carlile, Sinead A. O’Rourke, Chloe Court, Brenda Morris, Gina Leisching, Gráinne Jameson, Sarah A. Connolly, Adam H. Dyer, John P. McGrath, Emma McNally, Olivia Sandby-Thomas, Anjali Yennemadi, Conor M. Finlay, Clíona Ní Cheallaigh, Jean Dunne, Cilian Ó Maoldomhnaigh, Laura E. Gleeson, Aisling Dunne, Nollaig Bourke, Reinout van Crevel, Donal J. Cox, Niall Conlon, Arjun Raj, Rachel M. McLoughlin, Joseph Keane, Sharee A. Basdeo
Dearbhla M. Murphy, Isabella Batten, Aoife O’Farrell, Simon R. Carlile, Sinead A. O’Rourke, Chloe Court, Brenda Morris, Gina Leisching, Gráinne Jameson, Sarah A. Connolly, Adam H. Dyer, John P. McGrath, Emma McNally, Olivia Sandby-Thomas, Anjali Yennemadi, Conor M. Finlay, Clíona Ní Cheallaigh, Jean Dunne, Cilian Ó Maoldomhnaigh, Laura E. Gleeson, Aisling Dunne, Nollaig Bourke, Reinout van Crevel, Donal J. Cox, Niall Conlon, Arjun Raj, Rachel M. McLoughlin, Joseph Keane, Sharee A. Basdeo
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Research Article Immunology Infectious disease

IFN-γ–induced trained immunity enhances killing of priority pathogens in healthy and genetically vulnerable individuals

Abstract

Infectious diseases remain a global health challenge, driven by increasing antimicrobial resistance and the threat of emerging epidemics. Mycobacterium tuberculosis and Staphylococcus aureus are leading causes of mortality worldwide. Trained immunity — a form of innate immune memory — offers a promising approach to enhance pathogen clearance. Here, we demonstrate that IFN-γ induces trained immunity in human monocytes through a mechanism involving mTORC1 activation, glutaminolysis, and epigenetic remodeling. Macrophages derived from IFN-γ–trained monocytes exhibited increased glycolytic activity with enhanced cytokine and chemokine responses upon stimulation or infection. Crucially, trained macrophages had increased production of reactive oxygen species, which mediated enhanced bactericidal activity against methicillin-resistant S. aureus and M. tuberculosis. Furthermore, ATAC-sequencing analysis of IFN-γ–trained macrophages revealed increased chromatin accessibility in regions associated with host defense. Last, IFN-γ training restored impaired innate responses in macrophages from individuals homozygous for the TIRAP 180L polymorphism, a genetic variant associated with increased susceptibility to infection. These findings establish IFN-γ as a potent inducer of trained immunity in human monocytes and support its potential as a host-directed strategy to strengthen antimicrobial defenses, particularly in genetically susceptible individuals and high-risk clinical contexts.

Authors

Dearbhla M. Murphy, Isabella Batten, Aoife O’Farrell, Simon R. Carlile, Sinead A. O’Rourke, Chloe Court, Brenda Morris, Gina Leisching, Gráinne Jameson, Sarah A. Connolly, Adam H. Dyer, John P. McGrath, Emma McNally, Olivia Sandby-Thomas, Anjali Yennemadi, Conor M. Finlay, Clíona Ní Cheallaigh, Jean Dunne, Cilian Ó Maoldomhnaigh, Laura E. Gleeson, Aisling Dunne, Nollaig Bourke, Reinout van Crevel, Donal J. Cox, Niall Conlon, Arjun Raj, Rachel M. McLoughlin, Joseph Keane, Sharee A. Basdeo

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Figure 5

IFN-γ training epigenetically alters MDM.

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IFN-γ training epigenetically alters MDM. Sorted monocytes (n = 3 donors...
Sorted monocytes (n = 3 donors) were left untrained (UT) or trained with IFN-γ (50 ng/mL) for 24 hours. Cells were differentiated into MDM. On day 6, ATAC-sequencing was performed to determine epigenetic differences between UT and IFN-γ–trained MDM. (A) Gene ontology analysis showing selected enriched cellular pathways for regions that greatly increase in accessibility (red; log2FC > 2), regions that increase in accessibility (orange; log2FC > 0), and regions that decrease in accessibility (blue; log2FC < 0) in IFN-γ–trained cells. (B) TOBIAS plot showing the increase (orange) or decrease (blue) in transcription factor binding in IFN-γ–trained cells compared with UT cells. (C) Graph showing the log2FC in accessibility of candidate genes in IFN-γ–trained cells compared with UT cells. The genes are grouped as surface marker genes (blue), cytokine and chemokine genes (green), transcription factor genes (purple), and genes associated with cell metabolism (pink). Each point reflects one donor. (D–F) Heatmaps showing row-normalized accessibility at statistically significantly differential peak regions within candidate genes in IFN-γ–trained cells compared with UT cells grouped by functional genes (D), metabolism genes (E), and genes associated with cell surface marker expression (F). Graphs in A–C show log2 fold changes in IFN-γ–trained cells compared with UT cells. Graphs in D–F show overall accessibility at peaks of interest in both UT and IFN-γ–trained cells (see Methods).