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This report is written by MaltSci based on the latest literature and research findings

How does trained immunity enhance immune responses? ​

Abstract ​

Trained immunity represents a transformative concept in immunology, redefining our understanding of innate immune responses. Traditionally associated with adaptive immunity, immune memory is now recognized as a feature of innate immune cells, such as monocytes and macrophages, which can undergo long-term epigenetic and metabolic reprogramming following initial pathogen exposure. This review provides a comprehensive overview of the mechanisms underlying trained immunity, highlighting the roles of epigenetic modifications, metabolic shifts, and cytokine production in enhancing immune responses. Key findings demonstrate that trained immunity not only improves responses to previously encountered pathogens but also confers broad protection against unrelated infections, a phenomenon termed heterologous protection. Factors influencing trained immunity, including pathogen exposure, vaccination strategies, and genetic predisposition, are examined to elucidate their impact on immune efficacy. The implications for vaccine design and therapeutic applications are profound, as leveraging trained immunity may lead to more effective vaccination strategies and novel therapeutic interventions for infectious diseases and inflammatory conditions. Understanding the complexities of trained immunity is essential for harnessing its potential in clinical settings, particularly in the face of emerging infectious diseases and rising antimicrobial resistance.

Outline ​

This report will discuss the following questions.

  • 1 引言
  • 2 Mechanisms of Trained Immunity
    • 2.1 Epigenetic Modifications
    • 2.2 Metabolic Reprogramming
    • 2.3 Cytokine Production
  • 3 Factors Influencing Trained Immunity
    • 3.1 Pathogen Exposure
    • 3.2 Vaccination Strategies
    • 3.3 Genetic Predisposition
  • 4 Trained Immunity in Infectious Diseases
    • 4.1 Bacterial Infections
    • 4.2 Viral Infections
    • 4.3 Fungal Infections
  • 5 Implications for Vaccination and Therapeutics
    • 5.1 Vaccine Design
    • 5.2 Potential Therapeutic Applications
    • 5.3 Challenges and Future Directions
  • 6 Summary

1 Introduction ​

The concept of trained immunity has emerged as a transformative paradigm in immunology, fundamentally reshaping our understanding of the innate immune system's capabilities. Traditionally, immune memory was considered a unique characteristic of the adaptive immune system, primarily associated with T and B cells. However, recent findings indicate that innate immune cells, such as monocytes and macrophages, can also develop a form of memory through epigenetic and metabolic reprogramming, enhancing their responses to subsequent encounters with pathogens [1][2]. This phenomenon, first recognized through studies on the Bacillus Calmette-Guérin (BCG) vaccine and various microbial stimuli, challenges the long-standing notion that immune memory is exclusive to adaptive immunity [3][4].

The significance of trained immunity extends beyond mere academic interest; it has profound implications for vaccine development and the management of infectious diseases. By leveraging the innate immune system's capacity to 'remember' prior exposures, researchers are exploring new avenues for creating vaccines that can provide broad, nonspecific protection against a variety of pathogens [5][6]. This capability is particularly crucial in the context of rising antimicrobial resistance and the increasing incidence of infectious diseases exacerbated by global health challenges, such as climate change [5].

Current research highlights the intricate mechanisms underlying trained immunity, including epigenetic modifications, metabolic reprogramming, and the production of pro-inflammatory cytokines [7][8]. These processes enable innate immune cells to mount enhanced responses not only to previously encountered pathogens but also to unrelated infections, thereby contributing to improved host defense [4]. Understanding these mechanisms is vital for harnessing trained immunity in clinical applications, particularly in designing effective vaccines and therapeutic strategies for infectious diseases and other health conditions [2][9].

This review is organized into several key sections that will provide a comprehensive overview of trained immunity. The first section will delve into the mechanisms of trained immunity, focusing on epigenetic modifications, metabolic reprogramming, and cytokine production. Following this, we will examine the various factors influencing trained immunity, including pathogen exposure, vaccination strategies, and genetic predisposition. The review will then explore the role of trained immunity in infectious diseases, detailing its effects on bacterial, viral, and fungal infections. Finally, we will discuss the implications of trained immunity for vaccination and therapeutics, addressing challenges and future directions in this burgeoning field. Through this structured approach, we aim to illuminate the potential of trained immunity as a pivotal component in enhancing immune responses and informing future therapeutic strategies.

2 Mechanisms of Trained Immunity ​

2.1 Epigenetic Modifications ​

Trained immunity enhances immune responses through a series of intricate epigenetic modifications that enable innate immune cells to acquire a memory-like phenotype. This process is characterized by long-term changes in gene expression and cellular physiology without permanent genetic alterations, distinguishing it from the adaptive immune response.

Epigenetic reprogramming in trained immunity involves several key mechanisms. One significant aspect is the role of long non-coding RNAs (LncRNAs), which act as molecular scaffolds that facilitate the assembly of chromatin-remodeling complexes. These complexes catalyze epigenetic changes on chromatin, leading to alterations in gene expression that bolster the immune response upon re-exposure to pathogens [10].

Additionally, trained immunity is associated with specific epigenetic marks, such as histone acetylation, which enhances the accessibility of certain genes related to immune function. For instance, the accumulation of H3K4me3 and H3K27Ac marks on immune gene promoters has been observed, indicating a primed state for heightened responsiveness [11]. These epigenetic modifications result in a transcriptional rewiring that prepares innate immune cells, such as monocytes and macrophages, to respond more effectively to subsequent infections [8].

Moreover, metabolic reprogramming accompanies these epigenetic changes. Following an initial stimulus, innate immune cells exhibit a shift towards increased glycolysis and the accumulation of metabolites from the tricarboxylic acid (TCA) cycle. This metabolic shift is crucial for providing the energy necessary for the enhanced production of pro-inflammatory cytokines and antimicrobial responses [12]. The interplay between epigenetic and metabolic pathways is essential for establishing and maintaining the trained immunity phenotype [13].

In summary, the enhancement of immune responses through trained immunity is driven by epigenetic modifications that alter gene expression patterns and metabolic reprogramming, enabling innate immune cells to mount more robust and effective responses to subsequent pathogen encounters. This phenomenon not only improves the immediate immune defense but also has implications for vaccine efficacy and the development of therapeutic strategies targeting various diseases [1][3][14].

2.2 Metabolic Reprogramming ​

Trained immunity refers to the long-term functional reprogramming of innate immune cells, allowing them to mount enhanced responses to subsequent challenges after initial exposure to pathogens or their ligands. This phenomenon is primarily mediated through metabolic and epigenetic reprogramming, which plays a crucial role in enhancing immune responses.

Metabolic reprogramming during trained immunity involves significant alterations in cellular metabolism, primarily characterized by a shift towards glycolysis, increased oxidative phosphorylation, and changes in lipid and amino acid metabolism. These metabolic changes provide the necessary energy and biosynthetic intermediates required for the enhanced production of pro-inflammatory cytokines and other immune mediators. For instance, it has been shown that monocytes and macrophages undergo a metabolic shift that increases glycolysis, which is crucial for generating ATP rapidly to support heightened immune functions during subsequent infections (Domínguez-Andrés et al., 2019) [15].

The induction of trained immunity is also associated with epigenetic modifications that affect gene expression. These modifications include changes in histone acetylation and DNA methylation patterns, which facilitate the transcription of genes associated with immune activation. For example, trained immunity leads to a reconfiguration of chromatin architecture that allows for increased accessibility of transcription factors to specific genes, thus enhancing their expression (Arts et al., 2016) [16]. This epigenetic rewiring is essential for sustaining the long-term memory of innate immune cells, enabling them to respond more effectively to future challenges.

Moreover, the integration of metabolic pathways with epigenetic regulation creates a feedback loop that sustains the enhanced responsiveness of innate immune cells. For example, metabolites generated during glycolysis can serve as signaling molecules that further influence epigenetic changes, thereby reinforcing the trained immunity phenotype (Ferreira et al., 2022) [17]. This interconnectedness underscores the importance of both metabolic and epigenetic reprogramming in the establishment and maintenance of trained immunity.

Trained immunity not only improves responses to reinfection by the same pathogen but also enhances resistance to unrelated pathogens, a phenomenon referred to as heterologous protection. This broadening of immune responses is particularly evident in individuals vaccinated with certain vaccines, such as Bacille Calmette-Guérin (BCG), which has been associated with increased protection against various infections beyond tuberculosis (Netea et al., 2024) [18].

In conclusion, the enhancement of immune responses through trained immunity is a complex interplay of metabolic reprogramming and epigenetic modifications. These processes enable innate immune cells to achieve a state of heightened readiness, allowing for a more robust and rapid response to subsequent infections, thereby playing a critical role in host defense and the potential development of novel therapeutic strategies targeting trained immunity.

2.3 Cytokine Production ​

Trained immunity represents a form of innate immune memory, characterized by enhanced responses of innate immune cells to subsequent challenges after initial stimulation. This phenomenon is particularly relevant in understanding how trained immunity enhances immune responses, especially through the production of cytokines.

One of the key mechanisms underlying trained immunity involves epigenetic and metabolic reprogramming of innate immune cells, such as monocytes and macrophages. Upon exposure to pathogens or vaccines, these cells undergo significant immunometabolic changes that lead to a heightened state of readiness for future encounters. Specifically, trained immunity is associated with increased production of pro-inflammatory cytokines, which are crucial for effective immune responses.

For instance, in studies examining the effects of trained immunity, it has been shown that exposure to stimuli like the Bacille Calmette-Guérin (BCG) vaccine leads to increased cytokine production in response to unrelated pathogens. This increase is mediated by epigenetic modifications, such as histone acetylation and lactylation, which enhance the transcription of genes associated with cytokine production. For example, lactylation of histone H3 at lysine residue 18 (H3K18la) has been identified as a significant marker of trained immunity, positively correlating with active chromatin and enhanced gene transcription necessary for robust cytokine responses upon restimulation [19].

Moreover, the role of specific cytokines in modulating trained immunity is critical. Interleukin-36γ (IL-36γ), a pro-inflammatory cytokine, has been demonstrated to induce trained immunity in primary human monocytes by promoting higher cytokine responses and activating metabolic pathways regulated by epigenetic modifications. This process is mediated through signaling pathways such as NF-κB and mTOR, which are pivotal for the metabolic reprogramming that accompanies trained immunity [20].

Conversely, certain anti-inflammatory cytokines, such as interleukin-38 (IL-38), can inhibit the induction of trained immunity, highlighting the delicate balance between pro-inflammatory and anti-inflammatory signals in regulating immune responses [20]. This interplay is crucial as it determines the extent of cytokine production and the overall efficacy of the immune response.

In summary, trained immunity enhances immune responses primarily through the epigenetic and metabolic reprogramming of innate immune cells, resulting in increased cytokine production. This reprogramming allows these cells to respond more effectively to subsequent infections, providing a mechanism by which the innate immune system can exhibit memory-like characteristics traditionally associated with adaptive immunity. The regulation of this process by various cytokines underscores the complexity of trained immunity and its potential implications for therapeutic strategies in infectious and inflammatory diseases [7][21][22].

3 Factors Influencing Trained Immunity ​

3.1 Pathogen Exposure ​

Trained immunity is characterized by the long-term reprogramming of innate immune cells, enabling them to mount enhanced responses upon subsequent encounters with various pathogens. This phenomenon represents a significant shift in our understanding of immune memory, traditionally attributed solely to the adaptive immune system. The enhancement of immune responses through trained immunity involves several critical factors influenced by pathogen exposure.

Firstly, trained immunity is induced through initial exposure to specific microbial stimuli, which can include infections or certain vaccines. This exposure leads to epigenetic and metabolic reprogramming of innate immune cells, such as monocytes and macrophages. These cells undergo modifications that result in a persistent state of heightened responsiveness to subsequent infections, even if the pathogens encountered differ from the original stimulus. For instance, exposure to the Bacillus Calmette-Guérin (BCG) vaccine not only provides protection against tuberculosis but has also been shown to confer protection against unrelated pathogens, such as malaria and SARS-CoV-2 (Kumar et al., 2024; Bhargavi & Subbian, 2024) [12][23].

The mechanisms underlying trained immunity include significant changes in chromatin structure and gene expression profiles within innate immune cells. This reprogramming facilitates enhanced production of pro-inflammatory cytokines, such as IL-1β, TNF, and IL-6, which are critical for an effective immune response (Murphy et al., 2021) [24]. Moreover, metabolic shifts towards glycolysis are observed, providing the necessary energy and intermediates for sustained immune activity (Ziogas & Netea, 2022) [25].

Furthermore, the nature of the antigenic stimuli plays a crucial role in shaping the trained immunity response. Different pathogens can elicit distinct training programs, leading to varied outcomes in immune responsiveness. For example, macrophages exposed to various antigens display unique profiles of pro-inflammatory, metabolic, and antimicrobial responses upon re-exposure (Kumar et al., 2024) [23]. This specificity indicates that the training effects are not uniform but rather tailored to the characteristics of the initial pathogen encountered.

Additionally, the implications of trained immunity extend beyond mere protection against reinfection; it can also influence the severity of immune-mediated diseases. Inappropriate activation of trained immunity may lead to excessive inflammation and contribute to chronic inflammatory conditions (Ochando et al., 2023) [1]. Thus, while trained immunity enhances the ability of innate immune cells to respond more robustly to infections, it also poses risks if dysregulated.

In summary, trained immunity enhances immune responses through epigenetic and metabolic reprogramming of innate immune cells following pathogen exposure. The specific characteristics of the pathogens encountered dictate the nature and effectiveness of the immune response, illustrating the complexity and adaptability of the innate immune system in providing protection against a diverse array of infectious agents.

3.2 Vaccination Strategies ​

Trained immunity enhances immune responses through a complex interplay of epigenetic and metabolic reprogramming of innate immune cells, which results in a long-term functional state characterized by heightened responsiveness to subsequent challenges. This phenomenon is distinct from the classical adaptive immune memory, as it primarily involves innate immune cells such as monocytes, macrophages, and natural killer cells. The concept of trained immunity underscores the ability of these cells to exhibit memory-like features, enabling them to respond more effectively to diverse pathogens after an initial exposure, such as through vaccination or infection [1][8][25].

The mechanisms underlying trained immunity involve significant alterations in gene expression and metabolic pathways. For instance, epigenetic modifications, including changes in histone acetylation and DNA methylation, play a crucial role in reprogramming innate immune cells. This reprogramming enhances their capacity to produce pro-inflammatory cytokines and other mediators upon re-exposure to pathogens [1][26]. Specifically, studies have shown that trained immunity can lead to increased biosynthesis of lipid mediators and alterations in metabolic processes, such as enhanced glycolysis, which are essential for effective immune responses [27][28].

Vaccination strategies that exploit the principles of trained immunity are emerging as a novel approach to enhance vaccine efficacy. Traditional vaccines primarily target specific pathogens through adaptive immune responses; however, trained immunity-related vaccines aim to induce broader, nonspecific immune protection against a variety of pathogens. For example, live attenuated vaccines like Bacillus Calmette-Guérin (BCG) have been shown to confer heterologous protection against infections beyond their primary target [3][29]. The BCG vaccine, initially developed for tuberculosis, exemplifies how certain vaccines can trigger trained immunity, leading to enhanced immune responses against unrelated pathogens through epigenetic reprogramming [8].

Recent studies also highlight the potential of new vaccine strategies designed specifically to induce trained immunity. These vaccines could leverage the innate immune memory to improve overall vaccine effectiveness, particularly in populations at risk for infections where traditional vaccines may be less effective [6][28]. Furthermore, the exploration of probiotics and other microbial products that stimulate trained immunity offers promising avenues for developing next-generation vaccines [30].

In conclusion, trained immunity represents a significant advancement in our understanding of immune responses, particularly how innate immune cells can be harnessed to provide enhanced protection against a range of pathogens. By integrating this concept into vaccination strategies, there is potential for creating more effective vaccines that utilize the innate immune system's ability to "remember" prior encounters with pathogens, thereby improving public health outcomes.

3.3 Genetic Predisposition ​

Trained immunity enhances immune responses through a series of epigenetic and metabolic reprogramming processes that occur in innate immune cells following initial exposure to pathogens or vaccines. This phenomenon allows these cells to respond more effectively to subsequent encounters with a variety of pathogens, providing a form of innate immune memory.

The underlying mechanisms of trained immunity involve significant changes at the molecular level. Epigenetic modifications, such as histone acetylation and DNA methylation, play a crucial role in altering gene expression profiles of innate immune cells, enabling them to mount a heightened response upon re-exposure to pathogens. These modifications are often triggered by initial stimulation with specific antigens or microbial components, leading to a persistent state of hyper-responsiveness in the trained immune cells [3][7][21].

Metabolic reprogramming is another key factor influencing trained immunity. Upon initial stimulation, innate immune cells undergo shifts in their metabolic pathways, such as increased glycolysis and oxidative phosphorylation. This metabolic shift not only provides the necessary energy for enhanced immune responses but also generates metabolic intermediates that are critical for the production of pro-inflammatory cytokines and other mediators essential for effective immune function [12][13].

Genetic predisposition can also significantly influence the extent and efficacy of trained immunity. Individual genetic variations may affect the ability of innate immune cells to undergo the necessary epigenetic and metabolic changes that characterize trained immunity. For instance, certain genetic backgrounds may enhance the responsiveness of immune cells to initial stimuli or modulate the expression of key regulatory genes involved in the trained immunity pathways [6][8].

Furthermore, environmental factors, such as previous infections, vaccination history, and even lifestyle choices, can shape the innate immune response and its capacity for trained immunity. These factors interact with genetic predispositions to determine the overall effectiveness of the trained immunity response, potentially leading to differences in susceptibility to infections and inflammatory diseases among individuals [25][31].

In summary, trained immunity enhances immune responses through a combination of epigenetic and metabolic reprogramming in innate immune cells, influenced by genetic predispositions and environmental factors. Understanding these mechanisms not only provides insights into the fundamental processes of immune memory but also opens avenues for therapeutic interventions and vaccine development aimed at harnessing the power of trained immunity.

4 Trained Immunity in Infectious Diseases ​

4.1 Bacterial Infections ​

Trained immunity represents a paradigm shift in our understanding of the innate immune system, illustrating its capacity for memory-like responses following exposure to pathogens. This phenomenon is characterized by long-term epigenetic and metabolic reprogramming of innate immune cells, particularly monocytes and macrophages, enabling them to mount enhanced responses upon subsequent encounters with the same or different pathogens. The mechanisms underlying trained immunity are crucial for understanding its role in enhancing immune responses against bacterial infections.

The concept of trained immunity was initially elucidated through various studies that demonstrated how prior exposure to specific stimuli could significantly alter the functionality of innate immune cells. For instance, exposure to β-glucan or Bacillus Calmette-Guérin (BCG) vaccine induces a state of trained immunity, resulting in increased production of pro-inflammatory cytokines and improved antimicrobial activities. This enhanced response is mediated by metabolic and epigenetic changes, including chromatin remodeling and alterations in gene expression, which facilitate a more robust inflammatory response upon reinfection [1][8].

In a study focusing on Listeria monocytogenes, mice that underwent training with β-glucan demonstrated increased myelopoiesis and elevated levels of inflammatory monocytes and polymorphonuclear neutrophils (PMNs) in their blood. Following a challenge with L. monocytogenes, trained mice exhibited preserved peripheral blood leukocyte counts and a more effective antimicrobial response, characterized by reduced bacterial burden in organs and a decrease in systemic inflammation [32]. This indicates that trained immunity not only enhances the quantity of immune cells but also their functional capabilities, leading to a more efficient clearance of bacterial pathogens.

Moreover, trained immunity has been shown to confer broad-spectrum protection against various bacterial infections. In preclinical models, training significantly improved survival rates and reduced the severity of infections caused by pathogens such as Staphylococcus aureus, Escherichia coli, and Pseudomonas aeruginosa [33]. The underlying mechanisms involve the activation of innate immune cells, leading to sustained blood antimicrobial responses and enhanced hematopoietic progenitor mobilization from the bone marrow [34].

Furthermore, the interplay between trained immunity and specific immune pathways has been highlighted in studies examining the role of interleukin-1 signaling. For example, the protection conferred by trained immunity in models of listeriosis was shown to be dependent on the signaling pathways activated by interleukin-1, which are critical for orchestrating the immune response [33].

In summary, trained immunity enhances immune responses to bacterial infections through a combination of epigenetic reprogramming, metabolic alterations, and the activation of key immune signaling pathways. This results in a more effective and sustained immune response, providing a strategic advantage in combating bacterial pathogens and suggesting potential avenues for therapeutic interventions aimed at harnessing or modulating trained immunity for improved disease resistance [7][26].

4.2 Viral Infections ​

Trained immunity refers to the long-term functional reprogramming of innate immune cells that enhances their response to subsequent infections or vaccinations. This phenomenon is characterized by epigenetic and metabolic changes within innate immune cells, such as monocytes and macrophages, which allow these cells to respond more effectively to diverse pathogens, including viruses.

The concept of trained immunity has gained significant attention in the context of viral infections. It has been shown that exposure to certain viruses can induce trained immunity, thereby providing enhanced nonspecific protection against subsequent infections with the same or different pathogens. For instance, studies indicate that after an initial encounter with a viral pathogen, innate immune cells undergo a process of epigenetic reprogramming, which results in an improved inflammatory response upon re-exposure to either the same or a heterologous virus (Taks et al. 2022) [35]. This reprogramming includes alterations in gene expression and metabolic pathways that facilitate a more robust immune response.

The mechanism of trained immunity involves several key processes. First, the initial exposure to a pathogen leads to chromatin remodeling in innate immune cells, which modifies the accessibility of specific genes associated with immune responses. This remodeling is accompanied by increased production of pro-inflammatory cytokines, such as interleukin-1β (IL-1β), which are crucial for activating and sustaining the immune response (Ochando et al. 2023) [1]. Additionally, the metabolic reprogramming of these cells enhances their capacity to produce energy and effector molecules necessary for combating infections.

Moreover, trained immunity has implications for vaccine development. Vaccines that induce trained immunity, such as the Bacillus Calmette-Guérin (BCG) vaccine, have demonstrated heterologous protective effects against various infections beyond those they are specifically designed to target. This characteristic is particularly relevant in the context of viral infections, where the training of innate immune cells can enhance the overall efficacy of vaccines against respiratory viruses, including SARS-CoV-2 (Netea et al. 2023) [29].

However, it is essential to note that while trained immunity can confer protective effects, its inappropriate activation can lead to excessive inflammation and contribute to the pathogenesis of various diseases, including autoimmune conditions and chronic inflammatory disorders (Ziogas et al. 2023) [7]. Thus, understanding the dual role of trained immunity in both enhancing protective immune responses and potentially exacerbating inflammatory diseases is critical for developing effective therapeutic strategies.

In summary, trained immunity enhances immune responses through epigenetic and metabolic reprogramming of innate immune cells, leading to improved responses to subsequent infections. This concept not only provides insights into the mechanisms of immune memory beyond the adaptive immune system but also opens new avenues for vaccine development and therapeutic interventions against viral infections.

4.3 Fungal Infections ​

Trained immunity is a functional state of the innate immune response characterized by long-term epigenetic reprogramming of innate immune cells, which enhances their ability to respond to subsequent encounters with pathogens. This concept, originally recognized in the context of infectious diseases, illustrates that innate immune cells such as monocytes, macrophages, and natural killer (NK) cells can develop a memory-like response after initial exposure to microbial stimuli, leading to improved immune responses against microbial pathogens upon re-stimulation [1].

In the context of fungal infections, trained immunity plays a significant role in modulating immune responses. The first documented instance of trained immunity was associated with the human fungal pathogen Candida albicans, where exposure led to enhanced immune status in innate immune cells [36]. Subsequent studies have demonstrated that this form of immune memory is not limited to classical immune cells but can also involve non-immune cells, such as fibroblasts, which are critical in the context of tissue repair and inflammation [37].

Fungal infections, particularly those caused by opportunistic pathogens like Aspergillus fumigatus, present a significant challenge, especially in immunocompromised individuals. The interaction between fungal components, such as β-glucans and chitin, and the host's immune system can program adaptive responses that enhance protection against fungal infections [38]. Specifically, β-glucans have been shown to induce trained immunity, resulting in enhanced phagocytosis and antimicrobial functions of macrophages, leading to improved clearance of fungal pathogens [39].

Research has indicated that trained immunity can enhance resistance to fungal infections through several mechanisms. For instance, exposure to β-glucans not only augments the host's innate immune response but also induces significant metabolic and epigenetic changes in immune cells, thereby improving their function against subsequent infections [40]. Furthermore, trained immunity can lead to increased production of pro-inflammatory cytokines and enhanced activation of pathways that regulate inflammation and host responses to infections [39].

The implications of trained immunity extend beyond just enhanced responses to fungal infections; it provides insights into potential therapeutic strategies for managing these infections, especially in populations at higher risk, such as those with weakened immune systems due to HIV, organ transplantation, or other immunosuppressive conditions [41]. The ability to harness trained immunity could pave the way for innovative interventions aimed at enhancing the host's defense mechanisms against fungal pathogens, potentially reducing the incidence and severity of infections [42].

In summary, trained immunity enhances immune responses against fungal infections by reprogramming innate immune cells through epigenetic and metabolic changes, leading to improved pathogen recognition, enhanced inflammatory responses, and greater overall resistance to infections. This novel understanding opens new avenues for therapeutic interventions in infectious diseases, particularly those caused by fungal pathogens.

5 Implications for Vaccination and Therapeutics ​

5.1 Vaccine Design ​

Trained immunity enhances immune responses through a process characterized by long-term epigenetic and metabolic reprogramming of innate immune cells. This phenomenon enables these cells to mount a more robust and rapid response upon subsequent encounters with pathogens, a capability traditionally attributed to the adaptive immune system. Specifically, trained immunity allows innate immune cells, such as monocytes and macrophages, to retain a form of "memory" that enhances their responsiveness to infections, thus providing a broader and more sustained protection against a variety of pathogens.

The mechanisms underlying trained immunity involve significant changes at both the epigenetic and metabolic levels. For instance, upon initial exposure to specific stimuli, such as vaccines or infections, innate immune cells undergo chromatin remodeling and altered gene expression, leading to an increased production of pro-inflammatory mediators and heightened antigen presentation capabilities. This reprogramming enhances the innate immune response not only to the original pathogen but also to unrelated pathogens, a concept known as heterologous protection[18][25].

In terms of vaccine design, the concept of trained immunity opens new avenues for developing vaccines that induce both traditional adaptive immunity and trained immunity. Vaccines such as the Bacillus Calmette-Guérin (BCG) and measles-containing vaccines have demonstrated the ability to provide protection against infections beyond their intended targets, highlighting the potential of trained immunity in vaccine efficacy[28]. This capability can be leveraged to create novel vaccines that enhance the innate immune response, providing a dual mechanism of action: a specific response to targeted pathogens and a broader nonspecific response against various infectious agents.

Furthermore, understanding the pathways involved in trained immunity can lead to innovative therapeutic strategies. For example, targeting specific immunological pathways or reversing epigenetic changes may help modulate trained immunity in conditions where it is either overly activated, contributing to chronic inflammation and autoimmune diseases, or underactivated, as seen in severe infections[7][43]. Thus, manipulating trained immunity holds promise not only for enhancing vaccine responses but also for developing treatments for a range of diseases, including cancer and inflammatory disorders[9].

In summary, trained immunity enhances immune responses through a sophisticated interplay of epigenetic and metabolic changes that enable innate immune cells to respond more effectively to pathogens. This understanding has significant implications for vaccine design, paving the way for innovative approaches that harness the potential of trained immunity to improve both vaccination strategies and therapeutic interventions against various diseases.

5.2 Potential Therapeutic Applications ​

Trained immunity represents a significant advancement in our understanding of the innate immune system, demonstrating that innate immune cells can undergo long-term functional reprogramming following exposure to certain pathogens or vaccines. This phenomenon leads to enhanced immune responses upon subsequent encounters with a variety of pathogens, thereby providing a form of "memory" akin to that of the adaptive immune system. The mechanisms underlying trained immunity involve extensive metabolic and epigenetic reprogramming of innate immune cells, such as monocytes and macrophages, resulting in increased production of pro-inflammatory cytokines and improved antigen presentation capabilities [8][43].

The implications of trained immunity for vaccination are profound. Vaccines that induce trained immunity, such as the Bacillus Calmette-Guérin (BCG) vaccine, have been shown to provide heterologous protection against unrelated pathogens, enhancing overall immune responsiveness [25][28]. This characteristic of trained immunity allows for a broader protective effect beyond the specific pathogen targeted by the vaccine. For instance, individuals vaccinated with live attenuated vaccines not only exhibit enhanced immunity to the target disease but also demonstrate reduced mortality from other infections [28].

In terms of therapeutic applications, trained immunity presents a dual opportunity. On one hand, it can be harnessed to boost vaccine efficacy. By strategically inducing trained immunity through specific vaccine formulations, it is possible to enhance the innate immune response, thereby improving the overall effectiveness of vaccination programs [7][30]. On the other hand, the inappropriate activation of trained immunity can lead to adverse effects, such as excessive inflammation in chronic diseases or autoimmune conditions. Thus, understanding the regulatory mechanisms of trained immunity could inform therapeutic strategies aimed at modulating this response to mitigate inflammatory diseases while still providing protective benefits against infections [1][2].

Recent studies have explored various approaches to utilize trained immunity therapeutically. For example, the combination of trained immunity inducers, such as probiotic peptidoglycan skeletons, with traditional vaccines has shown promise in enhancing protection against infections like methicillin-resistant Staphylococcus aureus (MRSA) by activating innate immune responses through pathways such as TLR2/JAK-STAT3 [30]. Furthermore, trained immunity has been implicated in cancer immunotherapy, where enhancing innate immune responses can potentially improve tumor control and patient outcomes [9].

In summary, trained immunity enhances immune responses through metabolic and epigenetic reprogramming of innate immune cells, leading to improved responses against a range of pathogens. This concept not only opens avenues for developing novel vaccination strategies but also provides insights into therapeutic interventions that could either amplify protective immune responses or dampen inappropriate inflammatory reactions in various disease contexts [4][6].

5.3 Challenges and Future Directions ​

Trained immunity refers to the long-term functional reprogramming of innate immune cells, enabling them to mount enhanced responses upon subsequent encounters with pathogens. This phenomenon is characterized by epigenetic and metabolic modifications that facilitate improved immune responses through mechanisms such as chromatin remodeling and altered gene expression. In the context of vaccination and therapeutics, trained immunity offers significant implications and potential challenges.

One of the primary ways trained immunity enhances immune responses is through the reprogramming of innate immune cells such as monocytes, macrophages, and dendritic cells. These cells undergo extensive metabolic and epigenetic changes after an initial exposure to a stimulus, such as a vaccine or infection. This reprogramming results in an augmented inflammatory response and a heightened capacity to respond to a variety of pathogens, which is particularly beneficial in situations where rapid immune activation is crucial (Netea et al. 2024; Ziogas et al. 2023). For instance, the Bacillus Calmette-Guérin (BCG) vaccine has been shown to induce trained immunity, providing heterologous protection against infections beyond its intended purpose (Netea et al. 2022).

In terms of vaccination, the induction of trained immunity can enhance the efficacy of vaccines by promoting a broader immune response. Vaccines that can induce trained immunity may lead to improved protection against unrelated pathogens, a concept known as heterologous protection (Netea et al. 2024; Ziogas & Netea 2022). This can be particularly advantageous in the context of emerging infectious diseases, where rapid and robust immune responses are necessary to control outbreaks. However, the challenge lies in ensuring that the training of the immune system does not lead to excessive inflammation or autoimmunity, as dysregulated trained immunity can contribute to chronic inflammatory diseases (Bekkering et al. 2021).

Future directions in the field of trained immunity research include the development of novel vaccines designed specifically to harness this phenomenon. These vaccines could be engineered to enhance both innate and adaptive immune responses, potentially leading to better outcomes in preventing infections and managing diseases (Netea et al. 2024; Domínguez-Andrés et al. 2021). Furthermore, understanding the mechanisms underlying trained immunity can provide insights into therapeutic strategies for diseases characterized by inappropriate immune activation, such as autoimmune disorders and cancer (Mourits et al. 2018).

Despite the promise of trained immunity, several challenges remain. The precise mechanisms governing the induction and regulation of trained immunity are still not fully understood, which complicates the development of targeted interventions (Fok et al. 2018). Additionally, individual variability in immune responses, particularly among different age groups or those with underlying health conditions, poses a significant challenge in the application of trained immunity strategies (Bulut et al. 2020).

In summary, trained immunity represents a novel approach to enhancing immune responses through the reprogramming of innate immune cells. Its implications for vaccination and therapeutics are profound, offering potential pathways for improved disease prevention and treatment. However, addressing the challenges associated with dysregulation and individual variability will be crucial for the successful implementation of trained immunity in clinical settings.

6 Conclusion ​

The exploration of trained immunity has unveiled significant insights into the capabilities of the innate immune system, demonstrating that innate immune cells can develop a form of memory that enhances their responses to subsequent infections. Key findings indicate that epigenetic modifications and metabolic reprogramming are central to this process, enabling innate immune cells such as monocytes and macrophages to mount robust responses not only to previously encountered pathogens but also to unrelated ones. Current research emphasizes the potential of trained immunity in the context of infectious diseases, revealing its implications for vaccine design and therapeutic strategies. However, challenges remain, particularly regarding the regulation of trained immunity to prevent excessive inflammation or autoimmunity. Future research should focus on developing vaccines that leverage trained immunity and understanding individual variability in immune responses, paving the way for innovative approaches to disease prevention and treatment. This evolving field holds promise for enhancing public health outcomes by harnessing the innate immune system's remarkable capacity for memory and adaptability.

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