TLR Agonists as Mediators of Trained Immunity: Mechanistic Insight and Immunotherapeutic Potential to Combat Infection

Abstract

Despite advances in critical care medicine, infection remains a significant problem that continues to be complicated with the challenge of antibiotic resistance. Immunocompromised patients are highly susceptible to development of severe infection which often progresses to the life-threatening condition of sepsis. Thus, immunotherapies aimed at boosting host immune defenses are highly attractive strategies to ward off infection and protect patients. Recently there has been mounting evidence that activation of the innate immune system can confer long-term functional reprogramming whereby innate leukocytes mount more robust responses upon secondary exposure to a pathogen for more efficient clearance and host protection, termed trained immunity. Toll-like receptor (TLR) agonists are a class of agents which have been shown to trigger the phenomenon of trained immunity through metabolic reprogramming and epigenetic modifications which drive profound augmentation of antimicrobial functions. Immunomodulatory TLR agonists are also highly beneficial as vaccine adjuvants. This review provides an overview on TLR signaling and our current understanding of TLR agonists which show promise as immunotherapeutic agents for combating infection. A brief discussion on our current understanding of underlying mechanisms is also provided. Although an evolving field, TLR agonists hold strong therapeutic potential as immunomodulators and merit further investigation for clinical translation.

Pattern recognition receptors in health and diseases

“… 444 Clinically, PRR agonists can be potentially used not only as therapeutic agents to treat but also as adjuvants in conjunction with other immunotherapies. 445 , 446 Due to the instability and drug resistance of existing drugs, some adjuvants targeting PRRs emerge as the times require. A TLR3-specific adjuvant, ARNAX, can enhance DC priming and CTL proliferation without cytokine toxicity.…”

Toll-Like Receptors: General Molecular and Structural Biology

“…Nowadays, a wide range of TLR agonists comprising CU-CPT22, SMU-Z1, CU-T12-9, Pam 2 Cys (protects against influenza virus with long-term protectivity and secondary bacterial infections caused by Streptococcus pneumoniae) and Pam 3 CSK 4 (TLR1/TLR2 stimulators), Pam 3 Cys (TLR2/TLR6 stimulator), polyinosinic : poly-cytidylic acid (Poly(I : C) a synthetic dsRNA molecule which activates TLR3 provides protection against viral infections [178]), CU-CPT4a (prevents binding of dsRNA to TLR3) [8,177,[179][180][181], monophosphoryl lipid A (MPLA) (structurally resembles LPS and provides protection against viruses such as influenza virus; fungi like Candida albicans; Gramnegative bacteria, e.g., Ps.aeruginosa; and Gram-positive bacteria e.g., Staphylococcus aureus [182][183][184]. MPLA can act as an effective adjuvant in vaccines against malaria, HPV, and hepatitis B [185,186]); TH1020 (inhibits TLR5 dimerization); and imiquimod (a synthetic imidazoquinoline) (TLR7 agonist and antagonist), and imidazoquinoline-based agents (TLR8 agonists and antagonists) are produced and some of them are approved by FDA for their use as vaccine adjuvants [8,177,[179][180][181]. All in all, the ongoing studies provide us an interesting promise to use TLR agonists, antagonists, and vaccine adjuvants as effective immunomodulators and therapeutics for treating infectious and autoimmune diseases, cancers, and other inflammatory diseases and disorders.…”

“…In recent years, the application of TLR agonists as distinctive immunomodulator agents represents a new option for induction of immune responses and effective vaccine adjuvants [ 177 ]. TLRs are versatile and invaluable biomolecules which have their own molecular and structural biology.…”

Recent Insights Into the Molecular Mechanism of Toll-Like Receptor Response to Dengue Virus Infection

“…The concept of trained immunity or innate immune memory is not only present in plants or invertebrates, but also in mammals ( Quintin et al, 2014 ; Netea et al, 2016 ). TLRs are considered as the important triggerering molecule of trained immunity ( Sanchez-Ramon et al, 2018 ), and have been dicussed in several recently published reviews ( Netea et al, 2020 ; Owen et al, 2020 ; Pulendran et al, 2021 ). TLR agonists as vaccine adjuvants are currently under investigation for different human vaccines and appear as promising in the vaccine study ( Bendelac and Medzhitov, 2002 ; Duthie et al, 2011 ; Pulendran et al, 2021 ).…”