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 6

IFN-γ–induced trained immunity in donors with all TIRAP S180L polymorphism genotypes and enhanced killing of S. aureus.

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IFN-γ–induced trained immunity in donors with all TIRAP S180L polymorphi...
Enriched monocytes from donors with different genotypes of the TIRAP S180L polymorphism were left untrained (UT; white) or trained with IFN-γ (10 ng/mL; gray) for 24 hours. Cells were differentiated into MDM. (D–G) On day 6, MDM were stimulated with irradiated M.tb (10 μg/mL) for 24 hours. (H) On day 7, MDM were infected with S. aureus (USA300; MOI 100:1) for 4 hours, and bacterial burden was measured by CFU enumeration. (A–C) Expression of HLA-DR (A), CD40 (B), or CD86 (C) on unstimulated MDM of day 7 measured by flow cytometry grouped by TIRAP genotype. (D–G) TNF (D), IL-6 (E), IL-1β (F), or IL-10 (G) measured by ELISA grouped by genotype. (H) The intracellular bacterial burden of S. aureus within MDM was measured by CFU enumeration and grouped by TIRAP genotype graphed (compared with untrained MDM). TIRAP S180–homozygous (wild-type; SS, n = 11), S180L–heterozygous (SL, n = 8), or S180L–homozygous (LL, n = 6) individuals are plotted with each dot representing a single donor and paired data joined by a line. (H) Data show n = 3 (n = 1 SS, n = 1 SL, n = 1 LL). *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001 determined using a 2-way ANOVA with Tukey’s multiple-comparison test. (A and D) Data were analyzed by 2-way ANOVA; however, results were not statistically significant. #P < 0.05, paired t test comparing SS UT MDM with LL UT MDM (A), or SS UT MDM stimulated with M.tb with LL UT MDM stimulated with M.tb (D).