Scientists have discovered a groundbreaking approach to fighting drug-resistant infections by strengthening the body's own defense systems rather than relying solely on antibiotics. Researchers at Trinity College Dublin's Translational Medicine Institute found that they could "train" immune cells called macrophages to become faster and more effective at killing dangerous bacteria like methicillin-resistant Staphylococcus aureus (MRSA) and Mycobacterium tuberculosis, the bacterium that causes tuberculosis (TB). The study, published on World TB Day 2026 in the journal JCI Insight, offers a new strategy as antibiotic resistance continues to rise worldwide .

What Is "Trained Immunity" and How Does It Work?

Trained immunity is a process where the body's early immune system, called the innate immune system, "learns" from past infections and responds better the next time. The research team, led by Dr. Sharee Basdeo, focused on macrophages, which are immune cells that act like "clean-up crews" that find, engulf, and destroy harmful microbes. The scientists trained these macrophages using an immune protein called interferon-gamma (IFN-gamma), which acts as an "alert signal" to reprogram the cells .

When macrophages undergo this training, they become "reprogrammed" so that they react faster, respond more strongly, and kill microbes more effectively. This is particularly exciting because it targets the host, not the bacteria, meaning it could work against a range of drug-resistant pathogens, not just one specific strain .

How Do Trained Macrophages Actually Kill Bacteria More Effectively?

The research revealed several specific ways that trained macrophages become more powerful infection fighters. When exposed to bacteria like TB or MRSA, IFN-gamma trained macrophages showed multiple enhanced abilities:

• Stronger immune signals: Trained macrophages produced stronger signals that activate and attract other immune cells when exposed to bacteria.
• Increased energy production: They enhanced their rate of glycolysis, the process of breaking down glucose into energy needed for fighting infection.
• Bacterial-killing chemicals: They produced more reactive oxygen species (ROS), a bleach-like substance that cells make to kill bacteria.
• Metabolic fuel switching: During training, macrophages used glutamine as a key fuel source, and they underwent epigenetic changes that made infection-fighting genes easier to access and use.

The improved bacterial killing resulting from IFN-gamma training depends on ROS production. When researchers tested macrophages from a patient with a genetic mutation that prevents ROS production, the training did not enhance MRSA killing, confirming that this bacterial-killing chemical is essential to the process .

Why This Matters for People Vulnerable to Infection

One of the most promising aspects of this research is that the training effect works even in people who are typically more susceptible to infection. The team collected blood from donors who have a genetic mutation that leaves them more vulnerable to infections. When they trained macrophages from these donors with IFN-gamma, the results were encouraging: the cells produced better immune responses to TB and showed an enhanced ability to kill MRSA .

"This work is particularly exciting because it tackles antimicrobial resistance by targeting the host rather than the bacteria, meaning it could be effective against a range of drug-resistant pathogens. Crucially, we observed this training effect in cells from individuals who are typically more susceptible to infection, suggesting that immune training could help strengthen responses in vulnerable individuals," said Dr. Dearbhla Murphy, postdoctoral research fellow and lead author of the study.

Dr. Dearbhla Murphy, Postdoctoral Research Fellow at Trinity College Dublin

How Could This Treatment Be Used in Practice?

The research team envisions immune training as a complementary therapy that could be given alongside antibiotics to help people with drug-resistant TB and other infections. TB remains the leading cause of death from a single infectious agent worldwide, with over 1 million people dying from TB every year. The disease is particularly difficult to treat, and this challenge is growing because of antibiotic-resistant TB strains .

"Our innate immune response is so crucial in the fight against TB. It dictates whether or not you become sick with the disease. This study is exciting because it shows that we can boost the function of a key innate immune cell, a macrophage, by training it with IFN-gamma. This makes the macrophage faster and stronger at responding when it becomes infected," explained Dr. Sharee Basdeo, Assistant Professor in the School of Medicine and senior author.

Dr. Sharee Basdeo, Assistant Professor in the School of Medicine at Trinity College Dublin

What's Next for This Research?

The team plans to investigate whether IFN-gamma training helps macrophages kill other pathogens beyond bacteria, including viruses and fungi. This could expand the potential applications of immune training far beyond TB and MRSA. The approach represents a fundamental shift in how scientists think about fighting infections, moving away from the traditional focus on killing bacteria with drugs and toward strengthening the body's natural defenses .

As antibiotic resistance continues to rise globally, strategies like trained immunity offer hope for people with drug-resistant infections who have limited treatment options. A single dose of IFN-gamma was able to train macrophages in the laboratory, suggesting that this approach could eventually become a practical clinical tool .