Novel Lipidated Imidazoquinoline TLR7/8 Adjuvants Elicit Influenza-Specific Th1 Immune Responses and Protect Against Heterologous H3N2 Influenza Challenge in Mice

Miller, Shannon M.; Cybulski, Van; Whitacre, Margaret; Bess, Laura S.; Livesay, Mark T.; Walsh, Lois; Burkhart, David J.; Bazin, Hélène G.; Evans, Jay T.

doi:10.3389/fimmu.2020.00406

Cited by 40 publications

(37 citation statements)

References 81 publications

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“…Neonates were also protected against polymicrobial sepsis when infection was initiated 24 h after treatment ( 66 ). It is also important to note that imiquimod may be an effective vaccine adjuvant strategy for influenza ( 176 ).…”

Section: Toll-like Receptor Agonist-mediated Trained Immunity and Promentioning

confidence: 99%

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

et al. 2021

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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.

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Section: Toll-like Receptor Agonist-mediated Trained Immunity and Promentioning

confidence: 99%

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

et al. 2021

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“…Some polysaccharides from plants, bacteria, yeasts, and synthetic sources can simulate and activate innate cell types, and regulate adaptive immunity [ 34 ]. Importantly, polysaccharides that help create a Th1-type cellular response have been considered strong adjuvant candidates in the use of vaccines against cancer, viruses, and bacteria [ 35 , 36 , 37 ]. In the current study, we found that ALP could induce the phenotypic maturation of DCs by stimulating the expression of cell surface molecules, antigen-presenting ability, and Th1-polarizing pro-inflammatory cytokines.…”

Section: Discussionmentioning

confidence: 99%

Annona muricata L.-Derived Polysaccharides as a Potential Adjuvant to a Dendritic Cell-Based Vaccine in a Thymoma-Bearing Model

et al. 2020

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Dendritic cells (DCs) are powerful antigen-presenting cells that are often used to evaluate adjuvants, particularly for adjuvant selection for various vaccines. Here, polysaccharides (named ALP) isolated from leaves of Annona muricata L., which are used in traditional medicine such as for bacterial infections and inflammatory diseases, were evaluated as an adjuvant candidate that can induce anti-tumor activity. We first confirmed the phenotypic (surface molecules, cytokines, antigen uptake, and antigen-presenting ability) and functional alterations (T cell proliferation/activation) of DCs in vitro. We also confirmed the adjuvant effect by evaluating anti-tumor activity and immunity using an ALP-treated DC-immunized mouse model. ALP functionally induced DC maturation by up-regulating the secretion of Th1-polarizing pro-inflammatory cytokines, the expression of surface molecules, and antigen-presenting ability. ALP triggered DC maturation, which is dependent on the activation of the MAPK and NF-κB signaling pathways. ALP-activated DCs showed an ample capacity to differentiate naive T cells to Th1 and activated CD8+ T cells effectively. The systemic administration of DCs that pulse ALP and ovalbumin peptides strongly increased cytotoxic T lymphocyte (CTL) activity (by 9.5% compared to that in the control vaccine groups), the generation of CD107a-producing multifunctional T cells, and Th1-mediated humoral immunity, and caused a significant reduction (increased protection by 29% over that in control vaccine groups) in tumor growth. ALP, which triggers the Th1 and CTL response, provides a basis for a new adjuvant for various vaccines.

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“…Both cells were stably transfected with the secreted alkaline phosphatase (SEAP) reporter gene under the transcriptional control of an NF‐kB response element. The level of SEAP protein released into the culture media was used to quantify the extent of TLR7 stimulation, which also represents the levels of NF‐κB activation (Miller et al., 2020). HEK‐Blue‐Null1‐v and HEK‐Blue mTLR7 cells (1 × 10 4 ) were plated in 96‐well plates and grown to 70% confluence.…”

Section: Methodsmentioning

confidence: 99%

Morphine‐mediated release of miR‐138 in astrocyte‐derived extracellular vesicles promotes microglial activation

Liao

Niu

et al. 2020

J of Extracellular Vesicle

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Opioids, such as morphine, are the mainstay for the management of postsurgical pain. Over the last decade there has been a dramatic increase in deaths related to opioid overdose. While opioid abuse has been shown to result in increased neuroinflammation, mechanism(s) underlying this process, remain less understood. In recent years, microRNAs have emerged as key mediators of gene expression regulating both paracrine signaling and cellular crosstalk. MiRNAs constitute the extracellular vesicle (EV) cargo and can shuttle from the donor to the recipient cells. Exposure of human primary astrocytes to morphine resulted in induction and release of miR‐138 in the EVs isolated from conditioned media of cultured astrocytes. Released EVs were, in turn, taken up by the microglia, leading to activation of these latter cells. Interestingly, activation of microglia involved binding of the GUUGUGU motif of miR138 to the endosomal toll like receptor (TLR)7, leading, in turn, to cellular activation. These findings were further corroborated in vivo in wildtype mice wherein morphine administration resulted in increased microglial activation in the thalamus. In TLR7−/− mice on the other hand, morphine failed to induce microglial activation. These findings have ramifications for the development of EV‐loaded anti‐miRNAs as therapeutics for alleviating neuroinflammation in opioids abusers.

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Novel Lipidated Imidazoquinoline TLR7/8 Adjuvants Elicit Influenza-Specific Th1 Immune Responses and Protect Against Heterologous H3N2 Influenza Challenge in Mice

Cited by 40 publications

References 81 publications

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

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

Annona muricata L.-Derived Polysaccharides as a Potential Adjuvant to a Dendritic Cell-Based Vaccine in a Thymoma-Bearing Model

Morphine‐mediated release of miR‐138 in astrocyte‐derived extracellular vesicles promotes microglial activation

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