Lipopolysaccharide lipid A: A promising molecule for new immunity-based therapies and antibiotics

García-Vello, Pilar; Lorenzo, Flaviana Di; Zucchetta, Daniele; Zamyatina, Alla; Castro, Cristina De; Molinaro, Antonio

doi:10.1016/j.pharmthera.2021.107970

Cited by 33 publications

(20 citation statements)

References 235 publications

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“…The influence of the lipid A structure on LPS immunogenicity is well-described and currently it is believed that a six-acyl chain (hexa-acylated) lipid A is the most immunogenic form of LPS [ 29 , 30 ], [ 31 ]. This relationship provides a fundamental base for immune distinguish between pathogenic and non-pathogenic bacteria [ 32 ]. The hexa-acylated variant of lipid A is found in potent pathogens like Escherichia coli and Salmonella enterica serovar Typhimurium [ 33 ].…”

Section: Lipopolysaccharide—insights In the Structurementioning

confidence: 99%

“…For the purposes of this article, we will focus exclusively on LPS-recognizing receptor, namely the TLR4. TLR4s are expressed in many immune and non-immune mammalian cells, including macrophages, monocytes, peripheral blood lymphocytes, granulocytes, dendritic cells, microglia, astrocytes, brain endothelial cells, dermal micro-vessel endothelium, umbilical vein endothelium and adipocytes [ 32 ]. However, in the CNS, the largest pool of TLR4 is associated mainly with microglial cells [ 22 ].…”

Section: Cellular Recognition Of Lpsmentioning

confidence: 99%

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Lipopolysaccharide-Induced Model of Neuroinflammation: Mechanisms of Action, Research Application and Future Directions for Its Use

Skrzypczak-Wiercioch

Sałat

2022

Molecules

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Despite advances in antimicrobial and anti-inflammatory therapies, inflammation and its consequences still remain a significant problem in medicine. Acute inflammatory responses are responsible for directly life-threating conditions such as septic shock; on the other hand, chronic inflammation can cause degeneration of body tissues leading to severe impairment of their function. Neuroinflammation is defined as an inflammatory response in the central nervous system involving microglia, astrocytes, and cytokines including chemokines. It is considered an important cause of neurodegerative diseases, such as Alzheimer’s disease, Parkinson’s disease and amyotrophic lateral sclerosis. Lipopolysaccharide (LPS) is a strong immunogenic particle present in the outer membrane of Gram-negative bacteria. It is a major triggering factor for the inflammatory cascade in response to a Gram-negative bacteria infection. The use of LPS as a strong pro-inflammatory agent is a well-known model of inflammation applied in both in vivo and in vitro studies. This review offers a summary of the pathogenesis associated with LPS exposure, especially in the field of neuroinflammation. Moreover, we analyzed different in vivo LPS models utilized in the area of neuroscience. This paper presents recent knowledge and is focused on new insights in the LPS experimental model.

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Section: Lipopolysaccharide—insights In the Structurementioning

confidence: 99%

Section: Cellular Recognition Of Lpsmentioning

confidence: 99%

Lipopolysaccharide-Induced Model of Neuroinflammation: Mechanisms of Action, Research Application and Future Directions for Its Use

Skrzypczak-Wiercioch

Sałat

2022

Molecules

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“…However, the discovery of such unusual structural features is even more intriguing under biological and immunological points of view given that the TLR4/MD-2-mediated immunoactivity of an LPS almost entirely relies on the lipid A structure. In this regard, it is well established that lipid A species expressing less than six acyl chains (commonly defined as hypo-acylated lipid As) usually only poorly activate the human TLR4/MD-2-mediated immune response [ 10 – 13 ]. Here we have shown that Z. profunda SM-A87 expresses tetra- and penta-acylated lipid A and only one phosphate at position 1 of the reducing glucosamine, which also has been associated to a 100-fold decrease in the immunostimulatory activity of an LPS [ 42 ].…”

Section: Discussionmentioning

confidence: 99%

Section: Negative-ion Polaritymentioning

confidence: 99%

“…By contrast, LPS/lipid A structures that are ineffective in activating the TLR4-mediated signalling while keeping the capability to bind the receptor and to prevent the binding of agonistic LPS are defined as antagonists [10,11]. In this frame, the search for novel lipid A structures [10][11][12][13][14][15] that might possess any immunomodulatory activity towards TLR4/MD-2-dependent signalling is of high relevance for researchers of both the biomedical and pharmacological field who are attracted by the possibility to finely tune the immune response and, hence the inflammatory process(es). Consequently, due to the intrinsic nature of living and thriving in extreme habitats, deep-sea bacteria are evaluated as harmless for humans, therefore they can be considered as a "gold mine" for the discovery of new LPS and lipid A molecules to be isolated and analysed for the realization of new generation immune-therapeutics inspired by a natural source.…”

Section: Introductionmentioning

confidence: 99%

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Structural determination of the lipid A from the deep-sea bacterium Zunongwangia profunda SM-A87: a small-scale approach

et al. 2022

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Zunongwangia profunda SM-A87 is a deep-sea sedimentary bacterium from the phylum Bacteroidetes, representing a new genus of Flavobacteriaceae. It was previously investigated for its capability of yielding high quantities of capsular polysaccharides (CPS) with interesting rheological properties, including high viscosity and tolerance to high salinities and temperatures. However, as a Gram-negative, Z. profunda SM-A87 also expresses lipopolysaccharides (LPS) as the main components of the external leaflet of its outer membrane. Here, we describe the isolation and characterization of the glycolipid part of this LPS, i.e. the lipid A, which was achieved by-passing the extraction procedure of the full LPS and by working on the ethanol precipitation product, which contained both the CPS fraction and bacterial cells. To this aim a dual approach was adopted and all analyses confirmed the isolation of Z. profunda SM-A87 lipid A that turned out to be a blend of species with high levels of heterogeneity both in the acylation and phosphorylation pattern, as well as in the hydrophilic backbone composition. Mono-phosphorylated tetra- and penta-acylated lipid A species were identified and characterized by a high content of branched, odd-numbered, and unsaturated fatty acid chains as well as, for some species, by the presence of a hybrid disaccharide backbone.

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In Situ Neutralization and Detoxification of LPS to Attenuate Hyperinflammation

Song

et al. 2023

Advanced Science

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Hyperinflammation elicited by lipopolysaccharide (LPS) that derives from multidrug‐resistant Gram‐negative pathogens, leads to a sharp increase in mortality globally. However, monotherapies aiming to neutralize LPS often fail to improve the prognosis. Here, an all‐in‐one drug delivery strategy equipped with bactericidal activity, LPS neutralization, and detoxification is shown to recognize, kill pathogens, and attenuate hyperinflammation by abolishing the activation of LPS‐triggered acute inflammatory responses. First, bactericidal colistin results in rapid bacterial killing, and the released LPS is subsequently sequestered. The neutralized LPS is further cleared by acyloxyacyl hydrolase to remove secondary fatty chains and detoxify LPS in situ. Last, such a system shows high efficacy in two mouse infection models challenged with Pseudomonas aeruginosa. This approach integrates direct antibacterial activity with in situ LPS neutralizing and detoxifying properties, shedding light on the development of alternative interventions to treat sepsis‐associated infections.

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Lipopolysaccharide lipid A: A promising molecule for new immunity-based therapies and antibiotics

Cited by 33 publications

References 235 publications

Lipopolysaccharide-Induced Model of Neuroinflammation: Mechanisms of Action, Research Application and Future Directions for Its Use

Lipopolysaccharide-Induced Model of Neuroinflammation: Mechanisms of Action, Research Application and Future Directions for Its Use

Structural determination of the lipid A from the deep-sea bacterium Zunongwangia profunda SM-A87: a small-scale approach

In Situ Neutralization and Detoxification of LPS to Attenuate Hyperinflammation

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