Trained Immunity in Host Defense: Mechanisms, Pathogen Interactions, and Therapeutic Potential

Trained immunity refers to the functional reprogramming of innate immune cells-such as monocytes, macrophages, and natural killer cells-those results in a modulated, and often heightened, response to secondary stimuli. This phenomenon challenges the traditional view that immunological memory is restricted to the adaptive immune system and has emerged as a concept linking host defense, vaccination, and inflammatory disease. This review synthesizes current evidence on the molecular basis of trained immunity, including chromatin remodeling, histone modifications, and metabolic rewiring, and examines how bacteria, viruses, and fungi induce, evade, or exploit these programs. The dual contribution of trained immunity to protective host defense and to immunopathology is discussed, along with its implications for vaccine design-including heterologous protection reported after BCG vaccination-and its potential as a therapeutic target in infectious and inflammatory disease. Key gaps, particularly the duration and reversibility of the trained state, the distinction between trained immunity and related processes such as innate tolerance, and the need for validated biomarkers, are highlighted, together with priorities for future translational research.