lipid A
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Function
- main immunostimulatory component of bacterial lipopolysaccharide
- recognition of lipid A by the host immune system represents a fundamental event in recognition of gram-negative bacteria[1]
- lipid A from Alcaligenes faecalis is a ligand & weak agonist for TLR4 & a potent inducer of IgA without excessive inflammation[2]
* see Alcaligenes faecalis
Structure
- lipid A contains a glucosamine disaccharide backbone
- different levels of acylation & phosphorylation
- additional substituents on the sugar backbone (variable)
- immunostimulatory effects of lipid A depend on structure
- structural modification of lipid A can be achieved via chemical synthesis
Pharmacology
- monophosphoryl lipid A is a detoxified form of lipid A endotoxin used as a vaccine adjuvant on a mass scale in human populations[3]
- key to success of lipid A as a vaccine adjuvant is retaining function needed for stimulation of adaptive immune responses, while eliminating pro-inflammatory adverse effects
Adverse effects
- high levels of circulating bActerial liposaccharide containing lipid A as occurs in gram-negative septicemia can lead to septic shock
More general terms
References
- ↑ 1.0 1.1 Garcia-Vello P, Di Lorenzo F, Zucchetta D et al Lipopolysaccharide lipid A: A promising molecule for new immunity-based therapies and antibiotics. Pharmacol Ther. 2022 Feb;230:107970. PMID: https://www.ncbi.nlm.nih.gov/pubmed/34454000 Review.
- ↑ 2.0 2.1 Shimoyama A, Di Lorenzo F, Yamaura H et al Lipopolysaccharide from Gut-Associated Lymphoid-Tissue-Resident Alcaligenes faecalis: Complete Structure Determination and Chemical Synthesis of Its Lipid A. Angew Chem Int Ed Engl. 2021 Apr 26;60(18):10023-10031 PMID: https://www.ncbi.nlm.nih.gov/pubmed/33522128 PMCID: PMC8252424 Free PMC article
- ↑ 3.0 3.1 Ulrich JT, Myers KR. Monophosphoryl lipid A as an adjuvant. Past experiences and new directions. Pharm Biotechnol. 1995;6:495-524. PMID: https://www.ncbi.nlm.nih.gov/pubmed/7551233 Review.
Casella CR, Mitchell TC. Putting endotoxin to work for us: monophosphoryl lipid A as a safe and effective vaccine adjuvant. Cell Mol Life Sci. 2008 Oct;65(20):3231-40. PMID: https://www.ncbi.nlm.nih.gov/pubmed/18668203 PMCID: PMC2647720 Free PMC article. Review.
Bowen WS, Gandhapudi SK, Kolb JP, Mitchell TC. Immunopharmacology of lipid A mimetics. Adv Pharmacol. 2013;66:81-128. PMID: https://www.ncbi.nlm.nih.gov/pubmed/23433456 PMCID: PMC9536465 Free PMC article. Review.
Ji Y, An J, Hwang D et al Metabolic engineering of Escherichia coli to produce a monophosphoryl lipid A adjuvant. Metab Eng. 2020 Jan;57:193-202.. PMID: https://www.ncbi.nlm.nih.gov/pubmed/31786244 PMCID: PMC6960009 Free PMC article. - ↑ Shimoyama A, Fukase K. Lipid A-Mediated Bacterial-Host Chemical Ecology: Synthetic Research of Bacterial Lipid As and Their Development as Adjuvants. Molecules. 2021 Oct 18;26(20):6294. PMID: https://www.ncbi.nlm.nih.gov/pubmed/34684874 PMCID: PMC8538916 Free PMC article. Review.
- ↑ Sun X, Hosomi K, Shimoyama A, Yoshii K et al Alcaligenes lipid A functions as a superior mucosal adjuvant to monophosphoryl lipid A via the recruitment and activation of CD11b+ dendritic cells in nasal tissue. Int Immunol. 2024 Jan 29;36(1):33-43. PMID: https://www.ncbi.nlm.nih.gov/pubmed/38006376 PMCID: PMC10823578 Free PMC article.
- ↑ Strobl S, Hofbauer K, Heine H, Zamyatina A. Lipid A Mimetics Based on Unnatural Disaccharide Scaffold as Potent TLR4 Agonists for Prospective Immunotherapeutics and Adjuvants. Chemistry. 2022 Jun 21;28(35):e202200547. PMID: https://www.ncbi.nlm.nih.gov/pubmed/35439332 PMCID: PMC9325513 Free PMC article.