scholarly journals Toll-like receptor 4 agonist-based nanoparticles orchestrate protection against sepsis

2022 ◽  
Author(s):  
Yongxiang Zhao ◽  
Xinjing Lv ◽  
Jie Huang ◽  
Huiting Zhou ◽  
Hairong Wang ◽  
...  
Keyword(s):  
Lipid A ◽  
Severe Infection ◽  
Plga Nanoparticles ◽  
Great Promise ◽  
Toll Like Receptor 4 ◽  
E Coli ◽  
Monophosphoryl Lipid A ◽  
Tlr4 Agonist ◽  
Life Threatening ◽  
Plga Nanoparticle

AbstractSepsis, a life-threatening organ dysfunction induced by severe infection and uncontrolled host immune response, threatens the health of people all over the world. Herein, a type of nanoparticle formulation with simple components is synthesized by encapsulating monophosphoryl lipid A (MPLA), a TLR4 agonist, with poly(lactic-co-glycolic acid) (PLGA) nanoparticle. The obtained nanoparticles (MPLA@PLGA) could provide Escherichia coli (E. coli)-induced sepsis protection by regulating the immune system after sepsis challenge, including promoting the levels of various cytokines, boosting the percentage of natural killer cells and accelerating bacterial clearance. Notably, the survival mice pre-treated with these nanoparticles could resist repeated E. coli-induced sepsis. Our work therefore provides the great promise of MPLA@PLGA nanoparticles as a simple yet effective nano-drug for prevention and protection against E. coli-induced sepsis.

scholarly journals Lipopolysaccharide directly inhibits bicarbonate absorption by the renal outer medullary collecting duct

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Shuichi Tsuruoka ◽  
Jeffrey M. Purkerson ◽  
George J. Schwartz
Keyword(s):  
Lipid A ◽  
Kinase Inhibitor ◽  
Collecting Duct ◽  
Therapeutic Interventions ◽  
E Coli ◽  
Monophosphoryl Lipid A ◽  
Tlr4 Agonist ◽  
Medullary Collecting Duct ◽  
Phosphoinositide 3 Kinase

AbstractAcidosis is associated with E. coli induced pyelonephritis but whether bacterial cell wall constituents inhibit HCO3 transport in the outer medullary collecting duct from the inner stripe (OMCDi) is not known. We examined the effect of lipopolysaccharide (LPS), on HCO3 absorption in isolated perfused rabbit OMCDi. LPS caused a ~ 40% decrease in HCO3 absorption, providing a mechanism for E. coli pyelonephritis-induced acidosis. Monophosphoryl lipid A (MPLA), a detoxified TLR4 agonist, and Wortmannin, a phosphoinositide 3-kinase inhibitor, prevented the LPS-mediated decrease, demonstrating the role of TLR4-PI3-kinase signaling and providing proof-of-concept for therapeutic interventions aimed at ameliorating OMCDi dysfunction and pyelonephritis-induced acidosis.

scholarly journals Adjuvantation of an Influenza Hemagglutinin Antigen with TLR4 and NOD2 Agonists Encapsulated in Poly(D,L-Lactide-Co-Glycolide) Nanoparticles Enhances Immunogenicity and Protection against Lethal Influenza Virus Infection in Mice

Vaccines ◽  
2020 ◽  
Vol 8 (3) ◽  
pp. 519
Author(s):  
Amir Tukhvatulin ◽  
Alina Dzharullaeva ◽  
Alina Erokhova ◽  
Anastasia Zemskaya ◽  
Maxim Balyasin ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Lipid A ◽  
Influenza Virus Infection ◽  
Muramyl Dipeptide ◽  
Plga Nanoparticles ◽  
Influenza Hemagglutinin ◽  
Monophosphoryl Lipid A ◽  
Tlr4 Agonist

Along with their excellent safety profiles, subunit vaccines are typically characterized by much weaker immunogenicity and protection efficacy compared to whole-pathogen vaccines. Here, we present an approach aimed at bridging this disadvantage that is based on synergistic collaboration between pattern-recognition receptors (PRRs) belonging to different families. We prepared a model subunit vaccine formulation using an influenza hemagglutinin antigen incorporated into poly-(D,L-lactic-co-glycolic acid) (PLGA) nanoparticles adjuvanted with monophosphoryl lipid A (TLR4 agonist) and muramyl dipeptide (NOD2 agonist). The efficacy studies were conducted in comparison to control vaccine formulations containing individual PRR agonists. We show that the complex adjuvant based on TLR4 and NOD2 agonists potentiates proinflammatory cell responses (measured by activity of transcription factors and cytokine production both in vitro and in vivo) and enhances the phagocytosis of vaccine particles up to comparable levels of influenza virus uptake. Finally, mice immunized with vaccine nanoparticles containing both PRR agonists exhibited enhanced humoral (IgG, hemagglutination-inhibition antibody titers) and cellular (percentage of proliferating CD4+ T-cells, production of IFNɣ) immunity, leading to increased resistance to lethal influenza challenge. These results support the idea that complex adjuvants stimulating different PRRs may present a better alternative to individual PAMP-based adjuvants and could further narrow the gap between the efficacy of subunit versus whole-pathogen vaccines.

scholarly journals Adsorption of Toll-Like Receptor 4 Agonist to Alum-Based Tetanus Toxoid Vaccine Dampens Pro-T Helper 2 Activities and Enhances Antibody Responses

2015 ◽  
Vol 2015 ◽  
pp. 1-9 ◽  
Author(s):  
Juliana Bortolatto ◽  
Luciana Mirotti ◽  
Dunia Rodriguez ◽  
Eliane Gomes ◽  
Momtchilo Russo
Keyword(s):  
Tetanus Toxoid ◽  
Lipid A ◽  
Antibody Responses ◽  
Aluminum Salts ◽  
T Helper 2 ◽  
Monophosphoryl Lipid A ◽  
Tlr4 Agonist ◽  
Specific Antibody Production ◽  
Humoral Responses

Aluminum salts gels (alum) are TLR-independent adjuvants and have been used to boost antibody responses in alum-based vaccines such as diphtheria, pertussis, and tetanus toxoid (DPT) triple vaccine. However, the pro-Th2 activity of alum-based vaccine formulations has not been fully appreciated. Here we found that alum-based tetanus toxoid (TT) vaccine was biased toward a Th-2 profile as shown by TT-induced airway eosinophilic inflammation, type 2 cytokine production, and high levels of IgE anaphylactic antibodies. The adsorption into alum of prototypic TLR4 agonists such as lipopolysaccharides (LPS) derived fromEscherichia coliconsistently dampened TT-induced Th2 activities without inducing IFNγor Th1-like responses in the lung. Conversely, adsorption of monophosphoryl lipid A (MPLA) extracted fromSalmonella minnesota, which is a TIR-domain-containing adapter-inducing interferon-β- (TRIF-) biased TLR4 agonist, was less effective in decreasing Th-2 responses. Importantly, in a situation with antigenic competition (OVA plus TT), TT-specific IgG1 or IgG2a was decreased compared with TT sensitization. Notably, LPS increased the production of IgG1 and IgG2a TT-specific antibodies. In conclusion, the addition of LPS induces a more robust IgG1 and IgG2a TT-specific antibody production and concomitantly decreases Th2-cellular and humoral responses, indicating a potential use of alum/TLR-based vaccines.

scholarly journals Immunization with the Recombinant PorB Outer Membrane Protein Induces a Bactericidal Immune Response against Neisseria meningitidis

2002 ◽  
Vol 70 (8) ◽  
pp. 4028-4034 ◽  
Author(s):  
J. Claire Wright ◽  
Jeannette N. Williams ◽  
Myron Christodoulides ◽  
John E. Heckels
Keyword(s):  
Recombinant Protein ◽  
Neisseria Meningitidis ◽  
Outer Membrane ◽  
Lipid A ◽  
Meningococcal Infection ◽  
Native Protein ◽  
Monophosphoryl Lipid A ◽  
Porin Protein ◽  
Life Threatening ◽  
Porin Proteins

ABSTRACT Infections with Neisseria meningitidis are characterized by life-threatening meningitis and septicemia. The meningococcal porin proteins from serogroup B meningococci have been identified as candidates for inclusion in vaccines to prevent such infections. In this study, we investigated the vaccine potential of the PorB porin protein free of other meningococcal components. The porB gene from a strain of Neisseria meningitidis expressing the class 3 outer membrane porin protein (PorB3) was cloned into the pRSETB vector, and the protein was expressed at high levels in a heterologous host Escherichia coli. The recombinant protein was purified to homogeneity by affinity chromatography and used for immunization after incorporation into liposomes and into micelles composed either of zwitterionic detergent or nondetergent sulfobetaine. The immunogenicity of these preparations was compared to recombinant PorB protein adsorbed to Al(OH)3 adjuvant as a control. Although sera raised against the protein adsorbed to Al(OH)3 reacted with the purified recombinant protein, sera raised against liposomes and micelles showed greater activity with native protein, as measured by enzyme immunoassay with outer membranes and by whole-cell immunofluorescence. Reactivity with native protein was considerably enhanced by incorporation of the adjuvant monophosphoryl lipid A into the liposome or micelle preparations. Recognition of the native protein was in a serotype-specific manner and was associated with the ability of the antisera to promote high levels of serotype-specific complement-mediated killing of meningococci. These results demonstrate that the PorB protein should be considered as a component of a vaccine designed to prevent serogroup B meningococcal infection.

scholarly journals The TLR4 Agonist Monophosphoryl Lipid A Drives Broad Resistance to Infection via Dynamic Reprogramming of Macrophage Metabolism

2018 ◽  
Vol 200 (11) ◽  
pp. 3777-3789 ◽  
Author(s):  
Benjamin A. Fensterheim ◽  
Jamey D. Young ◽  
Liming Luan ◽  
Ruby R. Kleinbard ◽  
Cody L. Stothers ◽  
...  
Keyword(s):  
Lipid A ◽  
Monophosphoryl Lipid A ◽  
Monophosphoryl Lipid ◽  
Tlr4 Agonist ◽  
Resistance To Infection ◽  
Dynamic Reprogramming
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