Prophylactic and therapeutic insights into trained immunity: A renewed concept of innate immune memory

Abstract

Trained immunity is a renewed concept of innate immune memory that facilitates the innate immune system to have the capacity to remember and train cells via metabolic and transcriptional events to enable them to provide nonspecific defense against the subsequent encounters with a range of pathogens and acquire a quicker and more robust immune response, but different from the adaptive immune memory. Reversing the epigenetic changes or targeting the immunological pathways may be considered potential therapeutic approaches to counteract the hyper-responsive or hypo-responsive state of trained immunity. The efficient regulation of immune homeostasis and promotion or inhibition of immune responses is required for a balanced response. Trained immunity-based vaccines can serve as potent immune stimuli and help in the clearance of pathogens in the body through multiple or heterologous effects and confer protection against nonspecific and specific pathogens. This review highlights various features of trained immunity and its applications in developing novel therapeutics and vaccines, along with certain detrimental effects, challenges as well as future perspectives.

Keywords: Immunological memory; Trained immunity; epigenetics; immune cells; metabolic pathway; non-Immune cells; therapeutics; vaccines.

Figure 1.

The link between trained immunity with a variety of health and disease conditions. Stimulating or inhibiting the trained immunity with potential stimulators or inhibitors, respectively, has therapeutic potential. The increased heterogeneous immune response can be elicited via exploiting the stimulation of trained immunity. This heterogeneous response against various infections can be used to improve vaccines in the future. Some chronic autoimmune disorders, cardiovascular disease, food allergies, transplantation rejection are characterized via an inappropriately trained immune phenotype. Inhibiting trained immunity via potential inhibitors like rapamycin, metformin, ascorbate, butyrate, and 2-deoxy-d-glucose will be more useful in such cases. Figure was designed by Biorender.Com program (https://biorender.Com/) Accessed on 13 May 2021.

Figure 2.

Overview of a metabolic pathway in trained immunity. Glucose is a key substrate for cell metabolism and is responsible for two distinct metabolic pathways. Training of immune cells by the stimulus induces complex metabolic pathways, and accumulation of TCA cycle intermediates (fumarate, succinate, and α-ketoglutarate) acts as a cofactor in histone modification and induction of trained immunity. Metabolic products in glycolysis or OXPHOS pathway linking to immune metabolic activation and production result into a faster and more robust trained immune response.

Figure 3.

Trained immunity of immune cells with respect to epigenetic modification. Stimulation of naive immune cells causes metabolic reprogramming and histone modification. It would leave an epigenetic mark on activated genes. These genes are repressed later in the resting period, and the transcriptional machinery is inaccessible. Since the chromatin mark is partially removed following primary stimulation. During re-infection, trained immune cells may undergo rapid gene transcription as well as increased trimethylation and acetylation at promoter sites, establishing a link between immunometabolic activation and long-term epigenetic modification. Figure was designed by Biorender.Com program (https://biorender.Com/) Accessed on 13 May 2021.

Figure 4.

A schematic representation of trained immunity-signaling pathways and their therapeutic targets. PAMPs targeting a variety of PRRs results in the activation of various signaling pathways that facilitate trained immunity.