Boosting Toll-like receptor 4 signaling enhances the therapeutic outcome of antibiotic therapy in pneumococcal pneumonia

Casilag, Fiordiligie; Franck, Sebastian; Matarazzo, Laura; Figeac, Martin; Michelet, Robin; Kloft, Charlotte; Carnoy, Christophe; Sirard, Jean‐Claude

doi:10.1101/2020.02.18.955500

Cited by 5 publications

(13 citation statements)

References 40 publications

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“…Though it is impossible to predict exactly which patients will face an infectious challenge when, patients at risk for hospital acquired infections could be dosed at admission or prior to an event that may lead to infection, such as abdominal surgery. A recent study by Casilag et al shows that combination therapy with MPLA significantly augmented the efficacy of antibiotics leading to reduced bacterial burden and improved survival in a murine model of bacterial pneumonia, even when administered after induction of pneumonia (256). Therefore, treatment with immunomodulators such as TLR agonists and others may also be beneficial later in the course of sepsis to augment host innate immunity and improve outcomes.…”

Section: Discussionmentioning

confidence: 99%

The Metabolic Basis of Immune Dysfunction Following Sepsis and Trauma

et al. 2020

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Critically ill, severely injured and high-risk surgical patients are vulnerable to secondary infections during hospitalization and after hospital discharge. Studies show that the mitochondrial function and oxidative metabolism of monocytes and macrophages are impaired during sepsis. Alternatively, treatment with microbe-derived ligands, such as monophosphoryl lipid A (MPLA), peptidoglycan, or β-glucan, that interact with toll-like receptors and other pattern recognition receptors on leukocytes induces a state of innate immune memory that confers broad-spectrum resistance to infection with common hospital-acquired pathogens. Priming of macrophages with MPLA, CPG oligodeoxynucleotides (CpG ODN), or β-glucan induces a macrophage metabolic phenotype characterized by mitochondrial biogenesis and increased oxidative metabolism in parallel with increased glycolysis, cell size and granularity, augmented phagocytosis, heightened respiratory burst functions, and more effective killing of microbes. The mitochondrion is a bioenergetic organelle that not only contributes to energy supply, biosynthesis, and cellular redox functions but serves as a platform for regulating innate immunological functions such as production of reactive oxygen species (ROS) and regulatory intermediates. This review will define current knowledge of leukocyte metabolic dysfunction during and after sepsis and trauma. We will further discuss therapeutic strategies that target leukocyte mitochondrial function and might have value in preventing or reversing sepsis-and trauma-induced immune dysfunction.

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Section: Discussionmentioning

confidence: 99%

The Metabolic Basis of Immune Dysfunction Following Sepsis and Trauma

et al. 2020

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“…The pooled dataset used for the pharmacometric analysis comprised several individually performed in vivo studies: The combination of AMX administered by oral gavage (PK study: 0.4, 14 mg/kg; PD and survival study: 0.2, 0.4, 1.2 mg/kg) and a single dose of intraperitoneally administered MPLA (2.0 mg/kg) were investigated in a murine infection model [ 5 ] of two types of mice (RjOrl:Swiss, Balb/cJRj) being infected intranasally with S. pneumoniae (Minimal inhibitory concentration of AMX (MIC AMX ) = 0.016 mg/L) 12 h before treatment. Mice were either untreated or treated with AMX, MPLA or the combination as described in detail elsewhere ( Supplementary Section S1 , [ 5 ]). Total AMX concentrations were quantified in serum by a previously developed and validated liquid chromatography tandem mass spectrometry assay [ 16 ] including an in-study validation.…”

Section: Methodsmentioning

confidence: 99%

“…One frequently used drug to treat LRTI is amoxicillin (AMX), a well-established beta-lactam antibiotic classified as essential medicine by the World Health Organisation [ 4 ]. To sustain the drug’s effectiveness, the immunomodulatory characteristics of monophosphoryl lipid A (MPLA) were recently studied in combination with AMX [ 5 ]. MPLA, a toll-like receptor 4 (TLR4) agonist with a favorable safety profile [ 6 ], is already licensed as adjuvant with immunomodulatory characteristics for vaccines (Fendrix ® , hepatitis B [ 7 ]); Cervarix ® , human papilloma virus [ 8 ]).…”

Section: Introductionmentioning

confidence: 99%

“…MPLA, a toll-like receptor 4 (TLR4) agonist with a favorable safety profile [ 6 ], is already licensed as adjuvant with immunomodulatory characteristics for vaccines (Fendrix ® , hepatitis B [ 7 ]); Cervarix ® , human papilloma virus [ 8 ]). Based on in vivo data in a murine infection model, Casilag et al proposed that MPLA in monotherapy has the ability to stimulate the immune system, resulting in higher efficacy in terms of reduced bacterial numbers at the target sites lung and spleen as well as increased survival [ 5 ]. These effects were even more pronounced in combination with AMX [ 5 ].…”

Section: Introductionmentioning

confidence: 99%

“…Based on in vivo data in a murine infection model, Casilag et al proposed that MPLA in monotherapy has the ability to stimulate the immune system, resulting in higher efficacy in terms of reduced bacterial numbers at the target sites lung and spleen as well as increased survival [ 5 ]. These effects were even more pronounced in combination with AMX [ 5 ]. However, the mechanisms of these interactions are still unknown.…”

Section: Introductionmentioning

confidence: 99%

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A Model-Based Pharmacokinetic/Pharmacodynamic Analysis of the Combination of Amoxicillin and Monophosphoryl Lipid A Against S. pneumoniae in Mice

et al. 2021

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Combining amoxicillin with the immunostimulatory toll-like receptor 4 agonist monophosphoryl lipid A (MPLA) represents an innovative approach for enhancing antibacterial treatment success. Exploiting pharmacokinetic and pharmacodynamic data from an infection model of Streptococcus pneumoniae infected mice, we aimed to evaluate the preclinical exposure-response relationship of amoxicillin with MPLA coadministration and establish a link to survival. Antibiotic serum concentrations, bacterial numbers in lung and spleen and survival data of mice being untreated or treated with amoxicillin (four dose levels), MPLA, or their combination were analyzed by nonlinear mixed-effects modelling and time-to-event analysis using NONMEM® to characterize these treatment regimens. On top of a pharmacokinetic interaction, regarding the pharmacodynamic effects the combined treatment was superior to both monotherapies: The amoxicillin efficacy at highest dose was increased by a bacterial reduction of 1.74 log10 CFU/lung after 36 h and survival was increased 1.35-fold to 90.3% after 14 days both compared to amoxicillin alone. The developed pharmacometric pharmacokinetic/pharmacodynamic disease-treatment-survival models provided quantitative insights into a novel treatment option against pneumonia revealing a pharmacokinetic interaction and enhanced activity of amoxicillin and the immune system stimulator MPLA in combination. Further development of this drug combination flanked with pharmacometrics towards the clinical setting seems promising.

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Toll-Like Receptors as a Therapeutic Target in the Era of Immunotherapies

Farooq

Batool

Kim

et al. 2021

Front. Cell Dev. Biol.

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Toll-like receptors (TLRs) are the pattern recognition receptors, which are activated by foreign and host molecules in order to initiate the immune response. They play a crucial role in the regulation of innate immunity, and several studies have shown their importance in bacterial, viral, and fungal infections, autoimmune diseases, and cancers. The consensus view from an immunological perspective is that TLR agonists can serve either as a possible therapeutic agent or as a vaccine adjuvant toward cancers or infectious diseases and that TLR inhibitors may be a promising approach to the treatment of autoimmune diseases, some cancers, bacterial, and viral infections. These notions are based on the fact that TLR agonists stimulate the secretion of proinflammatory cytokines and in general, the development of proinflammatory responses. Some of the TLR-based inhibitory agents have shown to be efficacious in preclinical models and have now entered clinical trials. Therefore, TLRs seem to hold the potential to serve as a perfect target in the era of immunotherapies. We offer a perspective on TLR-based therapeutics that sheds light on their usefulness and on combination therapies. We also highlight various therapeutics that are in the discovery phase or in clinical trials.

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Boosting Toll-like receptor 4 signaling enhances the therapeutic outcome of antibiotic therapy in pneumococcal pneumonia

Abstract: 20

Cited by 5 publications

References 40 publications

The Metabolic Basis of Immune Dysfunction Following Sepsis and Trauma

The Metabolic Basis of Immune Dysfunction Following Sepsis and Trauma

A Model-Based Pharmacokinetic/Pharmacodynamic Analysis of the Combination of Amoxicillin and Monophosphoryl Lipid A Against S. pneumoniae in Mice

Toll-Like Receptors as a Therapeutic Target in the Era of Immunotherapies

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