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 2

IFN-γ training metabolically reprograms human macrophages.

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IFN-γ training metabolically reprograms human macrophages. (A and B) Sor...
(A and B) Sorted monocytes were left untreated or treated with IFN-γ (10 ng/mL; gray) for 15 minutes with or without rapamycin (50 nM). (A) Representative Western blot of phospho-S6 and β-actin density for each sample. (B) Phospho-S6 density normalized to β-actin, relative to untreated untrained control, measured by densitometry. (C–J) Enriched monocytes were left untrained (UT; white) or trained with IFN-γ (10 ng/mL; gray) for 24 hours. Cells were differentiated into MDM. (C–F) Relative expression (compared with untrained) of HK1 (C), GAPDH (D), PFKFB3 (E), or ATP5B (F) in unstimulated MDM on day 7 measured by qPCR. (G–J) On day 6, MDM metabolism was assessed using the Seahorse XFe24 analyzer. The arrows depict the time of stimulation and data analysis. (G and H) Relative (to untrained unstimulated) ECAR in response to LPS (10 ng/mL) (G) or irradiated M.tb (10 μg/mL) (H). (I and J) Relative (to untrained unstimulated) OCR in response to LPS (10 ng/mL) (I) or irradiated M.tb (10 μg/mL) (J). Each dot represents an individual donor, n = 4 (A and B), n = 6–8 (C–F), or n = 5 (G–J), with paired data joined by a line. *P < 0.05, **P < 0.01, ***P < 0.001 determined using a 2-way ANOVA with Fisher’s least significant difference (LSD) test (B and G–J) or a paired t test (C–F).