Maladaptive trained immunity in viral infections

Abstract

Trained immunity (TRIM) is a form of long-lasting functional reprogramming of innate immune cells and their progenitors that enhances responsiveness to subsequent stimuli. Although first characterized in myeloid cells, TRIM was recently extended to nonmyeloid cell types, including endothelial and glial cells, which also exhibit stimulus-driven, memory-like behavior. While initially recognized as a protective mechanism, particularly in the context of vaccines and acute infections, TRIM can also become maladaptive, promoting chronic inflammation, immune dysfunction, and disease. This Review focuses on virus-induced TRIM while also addressing microbial, metabolic, and endogenous inducers. We examine key ligands and receptors that initiate TRIM and dissect the associated signaling and epigenetic pathways. Importantly, we argue that maladaptive TRIM arises not from a specific ligand, receptor, or molecular event, but from contextual factors such as stimulus persistence, dose, tissue microenvironment, and preexisting inflammation. The nature of the secondary challenge also shapes whether a trained response is adaptive or maladaptive. We further discuss TRIM induction in the bone marrow, involvement of both myeloid and nonmyeloid cells, and the role of lipid rafts in sustaining TRIM. We review maladaptive TRIM's potential contribution to systemic diseases, such as atherosclerosis, diabetes, sepsis, cancer, and autoimmunity, along with its influence on viral vaccine responses. Finally, we outline potential strategies to redirect maladaptive TRIM and propose key outstanding questions for future research.

Figure 1. The spectrum of TRIM responses: from protection to pathology.

TRIM is initiated by microbial, vaccine-derived, or endogenous stimuli that trigger epigenetic and metabolic reprogramming of innate immune cells. The outcome of TRIM depends on the nature and duration of exposure. Single or brief exposures typically promote adaptive TRIM, enhancing immunity and protection. In contrast, prolonged or repetitive stimulation, such as that occurring in chronic infections such as HIV, can lead to maladaptive TRIM, characterized by persistent inflammatory responses that contribute to tissue damage and disease. This conceptual framework helps explain both beneficial and detrimental consequences of trained immunity across different contexts.

Figure 2. Balancing TRIM responses: context-dependent outcomes.

TRIM can result in either protective or maladaptive outcomes, depending on the context and duration of stimulation. Following exposure to infectious or endogenous stimuli, innate immune cells undergo epigenetic and metabolic reprogramming, leading to an initial inflammatory response. In the case of a single, transient exposure, such as vaccination or acute infection, this response typically resolves, resulting in protective TRIM. However, repeated or prolonged stimulation, as seen with chronic infections or frequent immunizations, may drive maladaptive TRIM characterized by sustained inflammation. The nature of the secondary stimulus also influences the outcome: successful resolution of infection supports adaptive responses, while persistent infection or excessive inflammatory signaling favors maladaptive TRIM. Understanding these dynamics is critical for optimizing vaccine strategies and managing chronic immune activation.