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Molecular targets and signaling pathways of trained immunity

Heather Brown, PhD
Tags: Immunity,

  • Trained immunity is the effective immunological response to a secondary antigen/insult after a primary exposure to an unrelated antigen/insult, providing immunological protection ranging from about 3 months to 1 year.
  • The mechanism of trained immunity exists on a cellular level via epigenetic and metabolic modifications that elicit a robust immune response to the secondary insult.
  • There is potential to target the pathways of trained immunity to develop treatments for health problems such as cancer, viral infection, and autoimmune disease.


If one decides to run a marathon, they will perform physical training for several months before the race. This training will acquaint them with the physical demands that running a marathon requires, so that they will have success when their fitness is tested on the day of the race. Likewise, if one begins a new job, they will likely complete a series of training sessions to become familiar with and proficient in the tasks required to successfully perform in the new role. In both scenarios, training describes the acquisition of a skill, knowledge, or experience by one who learns and practices something previously naïve to them. Broadly speaking, the act of "training" is exemplified in many different contexts, including within the cells and tissues of our bodies. For example, our immune system is constantly learning the molecular signatures associated with foreign invaders in order to identify and destroy them as efficiently as possible. The immune system accomplishes this via the innate immune system and the adaptive immune system. The innate immune system is the first line of defense against foreign invaders. It elicits a non-specific response and responds the same way to all pathogens. The adaptive immune response is the second line of defense that specifically targets the pathogen causing the infection. The pathogen is engulfed by an antigen-presenting cell (APC), then a small fragment of that pathogen is presented on the outside of the APC for the T cell to recognize; thus, resulting in T cell proliferation and antibody production specific to that pathogen. Since it is specific to the pathogen, the adaptive immune response is generally slower than the innate immune response; however, it is more accurate. The adaptive immune system also confers longer-term immunity toward specific pathogens since it can "remember" previously encountered pathogens and therefore deploy a swift and targeted immune response when faced with the same pathogen again. Figure 1 provides a brief overview of the innate and adaptive immune responses.






What is trained immunity?

Traditionally, the scientific consensus was that the innate immune system could not "learn" how to defeat pathogens in the way the adaptive immune response can. However, an increasing number of studies show that the innate immune response can result in an enduring and precise immunological memory response to unrelated secondary pathogens. This concept that the innate immune response demonstrates the ability to form immune memory and provide long-lasting protection against foreign invaders is termed "trained immunity." Specifically, this concept describes the long-term functional reprogramming of innate immune cells, which is initiated by a foreign antigen, leading to an altered response towards a second challenge after the return to a non-activated state (Fig. 2) (1). These innate immune cells (such as monocytes, macrophages, or natural killer cells) can be reprogrammed via epigenetic processes to open chromatin structures that allow the expression of inflammatory genes to defend a secondary insult (Fig. 2). Further, innate immune cells can be reprogrammed via metabolic pathways that result in better defense against a secondary insult as well (Fig. 2) (1).


Figure 2: Trained immunity results in effective defense against new pathogens. Initial pathogen exposure (A) results in functional reprogramming of innate immune cells via epigenetic modifications (B), gene expression changes (C), and metabolic changes (D). This causes an altered response towards a secondary pathogen exposure (E), via increased Akt/mTOR/HIF1 signaling pathway (F) and cytokine release (G, H).
For example, herpesvirus latency increases resistance to the bacterial pathogens Listeria monocytogenes and Yersinia pestis, via enhanced production of IFNγ and systemic activation of macrophages. Furthermore, the bacille Calmette-Guerin (BCG) vaccine, is a vaccine for tuberculosis disease, but evokes trained immunity resulting in a robust immune response to unrelated diseases such as bladder cancer and lymphoma (1,2). The trained immunity acquired from the BCG vaccine for treating cancer is so effective that it is now an FDA-approved treatment against many cancers, including melanoma and bladder cancer (1,2). Another example of trained immunity is the primary exposure to the fungal ligand β-glucan (present in the cell wall of the pathogen Candida albicans), which results in protection against subsequent infection with Staphylococcus aureus (3). Mechanistically, studies have found that these methods of trained immunity, specifically the BCG vaccine and β-glucan, trigger epigenetic modifications in histone tri-methylation at H3K4 via NOD2 and dectin signaling pathways, respectively. These changes then activate monocytes and macrophages, induce cytokine production, and switch cellular metabolic state from oxidative phosphorylation to aerobic glycolysis. These data provide evidence that infections by themselves or the immune system's exposure to immune-stimulatory agents (such as vaccines) can provoke specific protection against reinfection from a specific pathogen and non-specific protection against a subsequent challenge from a different pathogen. Given the likelihood that trained immunity plays a role in various diseases, understanding the molecular mechanisms that drive trained immunity can provide a framework to develop non-specific therapies to deploy in the clinic to treat various conditions.


Mechanisms of trained immunity:

The molecular mechanisms that drive trained immunity are beginning to be understood, yet many aspects of trained immunity remain opaque. To date, data show that the cell types that drive trained immunity are mainly monocytes/macrophages and NK cells. One of the first described mechanisms was the adaptive changes in macrophages associated with lipopolysaccharide (LPS) exposure, resulting in the silencing of inflammatory genes. This occurs via the accumulation of histone marks at promoters and enhancers (H3K27ac and H3K4me1) of genes that code for inflammatory proteins. For example, Candida albicans and fungal β-glucan trigger monocyte histone methylation changes, ultimately protecting against reinfection. For example, monocytes exposed to β-glucan in vitro respond to LPS with greater breadth 7 days after "priming" as the result of the activation of the Akt/mTOR and HIF1α pathway. Furthermore, monocytes exposed to β-glucan for 24 hours switch to aerobic glycolysis via epigenetic modification and maintain this metabolic state for at least 7 days after being "primed." These primed monocytes are more responsive to subsequent LPS exposure as measured by the increased amount of TNFα they secrete compared to un-primed cells. The switch to aerobic glycolysis during the first 24 hours of priming is required for monocytes to experience the epigenetic modifications and activation of the Akt/mTOR//HIF1α pathways to undergo training (1,3,4).


Examples of trained immunity in the clinic:

Harnessing the mechanisms of trained immunity has the potential to be efficacious for the treatment and prevention of many conditions. For example, inducing trained immunity to complement specific cancer therapies or to treat the immune challenges associated with sepsis could save many lives. Additionally, the mechanisms of trained immunity can be manipulated to dampen an overly trained innate immune state responsible for chronic inflammatory diseases. Increasing our understanding of the molecular targets and signaling pathways important for trained immunity will lead to advancements in therapies against many illnesses. Many labs are currently studying the mechanisms of trained immunity to develop clinical treatments. For example, scientists have discovered that administering β-glucan to mice increases IL-1β secretion and stimulates various cell proliferation-associated pathways, such as cell cycle genes, cholesterol biosynthesis, and glycolysis (1). These data and other studies have helped develop small molecule inhibitors to block IL-1β to decrease overall inflammation in diseases such as cancer via the trained immunity pathways (1). Another example of harnessing trained immunity in the clinic is the intentional exposure to the peptidoglycan component, muramyl dipeptide, to induce protection against Streptococcus pneumoniae and Toxoplasma gondii infections. This is currently under investigation in mice and humans to develop effective treatments for other fungal infections and malignant tumors (1). Since trained immunity heavily relies on epigenetic modifications of innate immune cells, targeting these epigenetic modifications in the clinic would be advantageous for treating many diseases driven by these epigenetic aberrations. For example, small molecules and antibodies can be used to target specific trained immunity pathways by targeting markers such as H3K4 trimethylation (1). Moreover, treatment with immunostimulating CpG oligodeoxynucleotides leads to protection against subsequent sepsis and Escherichia coli meningitis in mouse studies (3). Not only is trained immunity being harnessed to study and treat diseases in the context of increasing the immune response, it is also being studied in the context of dampening the immune response. For example, trained immunity is upregulated in some autoimmune conditions, thus we can target innate immune cells and regulate trained immunity to achieve long-term therapeutic benefits in various immune-related diseases such as inflammatory/autoimmune disorders, allergies, and cardiovascular disease. For example, immune training with LPS reduces inflammation and fibrosis in systemic sclerosis models by downregulating the production of cytokines such as IL-6, TNF, and IL-1β, simultaneously upregulating the production of the anti-inflammatory cytokine IL-10 (6). The benefits of utilizing the mechanisms of trained immunity are also being exploited as a potential solution for treating coronavirus infections. Training of the host's innate immune system can elicit immune protective effects in several cell types by activating specific signaling pathways such as cytokine release to attack a foreign antigen such as SARS-CoV-2 proteins (5). Overall, the concepts of trained immunity are utilized in clinics today. However, there is much more to understand to continue advancing current treatments and developing novel treatments.


What are the molecular targets and signaling pathways of trained immunity?

The main mechanisms by which trained immunity affects innate immune cells are epigenetic and metabolic changes. Typically, these changes are initiated via a ligand that binds a specific receptor, in turn, activating epigenetic and metabolic pathways to cause a cellular response (such as cytokine release or transcriptional changes). For example, the induction of trained immunity by microbial ligands such as LPS and PAMPs is facilitated by receptor signaling pathways that subsequently activate metabolic and epigenetic responses (1). Below are some specific pathways through which trained immunity occurs:
  • Dectin-1 dependent fungal pathway: β -glucans are recognized as Pathogen-associated molecular patterns (PAMPs) by macrophages through the Dectin-1 transmembrane receptor. Macrophage activation via dectin 1 induces specific epigenetic marks, including the histone marks H3K4me1, H3K4me3, and H3K27Ac, which lead to trained immunity (1).
  • NOD2: Muramyl dipeptide (MDP) is a PAMP that is characteristic of all bacteria and results in cytokine release from immune cells. Innate immune cell activation by MDP involves the cytoplasmic pattern recognition receptor (PRR) NOD2. NOD2 activation and signaling through NF-κB stimulates epigenetic rewiring of macrophages and induces trained immunity (1).
  • IL-1β: BCG induces epigenetic reprogramming in human monocytes in vivo, followed by functional reprogramming and protection against non-related viral infections, with a key role for IL-1β as a mediator of trained immunity responses (5, 6). In addition, β -glucan training increases IL-1β and IL-32.


How can I study molecular targets of trained immunity?

Studying molecular targets and signaling pathways implicated in trained immunity requires sensitive and specific reagents to provide reliable data to advance your study in a meaningful way. Enzo offers an extensive portfolio of reagents perfectly suited for your trained immunity research. For example, Enzo offers dozens of cytokine ELISAs with high sensitivity and specificity to detect diverse cytokines critical in the inflammatory and trained immunity pathways. In addition, Enzo offers immunomodulatory agents such as our TLRGRADE® LPS and ODN, as well as our interleukins that stimulate/inhibit specific pathways in trained immunity. In addition to understanding the pathways, Enzo also offers a variety of solutions to begin the drug discovery process and assess off-target effects/potential toxicity. Overall, Enzo provides complete solutions for revealing the mechanisms that drive trained immunity to identifying therapeutics that modulate trained immunity. Do you have questions about the available tools for your research? Do you need help in setting up your experiments? Do you want to learn more about our portfolio? Please reach out to our Technical Support Team, and we are happy to assist!

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Cited Sources:
1) Therapeutic targeting of trained immunity - PubMed (nih.gov)
2) BCG immunotherapy of bladder cancer: 20 years on - PubMed (nih.gov)
3) Defining trained immunity and its role in health and disease - PubMed (nih.gov)
4) Aerobic glycolysis: beyond proliferation - PubMed (nih.gov)
5) Trained Immunity: An Overview and the Impact on COVID-19 - PubMed (nih.gov)
6) BCG Vaccination Protects against Experimental Viral Infection in Humans through the Induction of Cytokines Associated with Trained Immunity - PubMed (nih.gov)
7) Innate immune memory in the brain shapes neurological disease hallmarks – PubMed (nih.gov)

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