The role of trained immunity in broad-spectrum antiviral defense against respiratory viral infections

Respiratory viral infections not only impose a global disease burden but also represent a primary risk source for pandemics caused by emerging and re-emerging pathogens. Current vaccine technologies exhibit insufficient broad-spectrum efficacy against highly variable viruses and unknown pathogens, revealing inherent limitations of antigen-dependent strategies. Thus, elucidating the compositional attributes and effector mechanisms of broad-spectrum protective immunity in the respiratory tract, and advancing novel intervention strategies, have become urgent priorities. Trained immunity, as an innate immune memory paradigm, has revolutionized the traditional immunological view that only adaptive immunity possesses memory. This mechanism confers nonspecific immune memory functions to macrophages, monocytes, natural killer cells, and respiratory structural cells through epigenetic remodeling and metabolic reprogramming, enabling enhanced responses to secondary heterologous infections. It provides new avenues for developing broad-spectrum vaccines and therapeutic approaches. For instance, live attenuated vaccines like BCG and certain viral vector vaccines have demonstrated the ability to induce such heterologous protection. However, research on trained immunity faces critical challenges: (1) mechanistic complexity: The dynamic regulatory principles underlying the induction, maintenance, and effector phases of trained immunity remain incompletely defined. Key processes include chromatin remodeling through histone modifications like H3K4me3 and metabolic shifts towards aerobic glycolysis. (2) Lack of standardized evaluation systems: Absence of validated biomarkers and quantitative assessment models hampers consistent measurement across studies. Potential solutions may involve utilizing multi-omics approaches to identify epigenetic signatures of tissue-resident cells or circulating free DNA. (3) Underexplored targeted induction strategies: Approaches to program “beneficial” trained immunity imprints—characterized by enhanced antiviral resistance coupled with improved inflammatory tolerance—require systematic exploration. This includes designing inducers that avoid excessive inflammation while promoting effective pathogen control. Overcoming these bottlenecks demands integration of multi-omics analyses, digital decoding of immune states, and precision modulation technologies. Promising strategies involve using engineered viral vectors with deleted specific genes or nanoparticle-encapsulated metabolites to target myeloid cells. By dissecting molecular switches governing “resistance-tolerance” bidirectional training and designing programmable inducers (e.g., engineered viral vectors, metabolic agonists), it may be possible to achieve broad-spectrum prevention against multiple respiratory pathogens. This review systematically examines the role of trained immunity in antiviral defense within the respiratory tract, aiming to inspire next-generation broad-spectrum vaccines and immunotherapeutic strategies capable of providing “one-to-many” protection against diverse viral threats.