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

## TL;DR

IFN-γ can train immune cells to better fight tuberculosis and MRSA, especially in people with genetic vulnerabilities.

## Contribution

IFN-γ is shown to induce trained immunity in human monocytes, enhancing antimicrobial defenses in genetically vulnerable individuals.

## Key findings

- IFN-γ induces trained immunity in monocytes via mTORC1 activation, glutaminolysis, and epigenetic changes.
- Trained macrophages show increased bactericidal activity against MRSA and M. tuberculosis through reactive oxygen species.
- IFN-γ training restores impaired immune responses in macrophages from individuals with the TIRAP 180L polymorphism.

## 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.

Immune cells that defend against early infection can be trained to better fight tuberculosis and MRSA, especially in vulnerable individuals.