When the Immune System Trains Too Hard

Trained Immunity, Immunometabolism, and the Energy Cost of Resilience

A new review in the Journal of Clinical Investigation (Sviridov, Netea & Bukrinsky, 2025) takes a deep dive into the fascinating world of trained immunity (TRIM)—the ability of our innate immune system to “remember” past exposures and respond more strongly the next time.

Unlike the adaptive immune system (with its antibodies and memory T cells), TRIM works through epigenetic and metabolic reprogramming of innate cells like monocytes and macrophages. In other words, our most ancient immune defenses can be “trained” by infections, vaccines, or even metabolic exposures.

The Double-Edged Sword of Training

TRIM can be a protector or a saboteur:

• Adaptive TRIM occurs after short, controlled exposures (such as BCG vaccination or acute viral infection). Cells shift their metabolism toward aerobic glycolysis, cholesterol biosynthesis, and fatty acid synthesis—fast, resource-hungry programs that enhance defense. If the challenge is brief and the system has enough energy to recover, this metabolic training makes us stronger.

  
  

• Maladaptive TRIM arises under persistent or excessive stimulation (e.g., HIV infection, chronic hyperglycemia, oxidized LDL, or constant saturated fat exposure). In these cases, the same metabolic pathways stay switched “on” without reprieve. Instead of resilience, the immune system becomes locked into a pro-inflammatory state, fueling chronic diseases such as atherosclerosis, diabetes, autoimmunity, and even long COVID.

The review highlights striking immunometabolism details:

• Palmitate (saturated fat) drives maladaptive TRIM via ceramide production; oleate (monounsaturated fat) can block this effect.

• Resveratrol (a polyphenol) enhances beneficial BCG-induced TRIM while suppressing maladaptive cholesterol-driven TRIM.

• High glucose reprograms bone marrow progenitors toward inflammatory phenotypes that worsen diabetes and vascular disease.

• Lipid rafts—cholesterol-rich membrane platforms—act as hubs for maladaptive TRIM signaling in HIV and atherosclerosis.

Energy and Substrate: The Missing Link

These insights fit squarely with the framework of Exposure-Related Malnutrition (ERM). ERM proposes that our ability to adapt to stress depends not just on the exposure itself, but on whether the body has enough energy and substrates to support recovery.

• With adequate reserves, the immune system can mount TRIM, then resolve inflammation, repair tissue, and reset balance.

• With scarce or mismatched resources, the same pathways become stuck. Cells cannot switch off glycolysis, cholesterol synthesis, or cytokine release—leading to maladaptive TRIM and a trajectory toward chronic disease.

In essence: energy sufficiency turns training into resilience; insufficiency turns training into exhaustion.

Why This Matters

The review underscores a truth that modern medicine is only beginning to embrace:

The outcome of an immune response is not dictated by the pathogen alone, but by the energetic context of the host.

This perspective opens doors for both prevention and therapy:

• Designing vaccines and adjuvants that harness adaptive TRIM without tipping into maladaptation.

• Using dietary and metabolic interventions (e.g., balancing fats, controlling glucose, leveraging plant polyphenols) to bias the immune system toward protective memory.

• Identifying metabolic and epigenetic “signatures” that predict when TRIM has gone wrong—offering a chance to intervene before inflammation becomes disease.

The Big Picture

The immune system’s ability to “train” itself is a marvel of biology. But like an athlete who overtrains without proper fuel or recovery, our cells can turn a survival skill into a liability.

The JCI review reminds us that immunity is never free—it carries an energy cost. The ERM framework adds that whether that cost strengthens us or breaks us depends on the balance between exposure load and resource availability.

In other words: resilience is not just about fighting; it’s about having enough energy to fight, repair, and recover.

📖 Reference

Sviridov D, Netea MG, Bukrinsky MI. Maladaptive trained immunity in viral infections. J Clin Invest. 2025;135(17):e192469. https://doi.org/10.1172/JCI192469

#Trained Immunity, #Immunometabolism, #Maladaptive Inflammation, #Exposure-Related Malnutrition (ERM), #Energy Allocation