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Fortifying the barrier: the impact of lipid A remodelling on bacterial pathogenesis.

ABSTRACT: Gram-negative bacteria decorate their outermost surface structure, lipopolysaccharide, with elaborate chemical moieties, which effectively disguises them from immune surveillance and protects them from the onslaught of host defences. Many of these changes occur on the lipid A moiety of lipopolysaccharide, a component that is crucial for host recognition of Gram-negative infection. In this Review, we describe the regulatory mechanisms controlling lipid A modification and discuss the impact of modifications on pathogenesis, bacterial physiology and bacterial interactions with the host immune system.

SUBMITTER: Needham BD

PROVIDER: S-EPMC6913092 | biostudies-literature | 2013 Jul

REPOSITORIES: biostudies-literature

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Fortifying the barrier: the impact of lipid A remodelling on bacterial pathogenesis.

Needham Brittany D BD Trent M Stephen MS

Nature reviews. Microbiology 20130610 7

Gram-negative bacteria decorate their outermost surface structure, lipopolysaccharide, with elaborate chemical moieties, which effectively disguises them from immune surveillance and protects them from the onslaught of host defences. Many of these changes occur on the lipid A moiety of lipopolysaccharide, a component that is crucial for host recognition of Gram-negative infection. In this Review, we describe the regulatory mechanisms controlling lipid A modification and discuss the impact of mod ...[more]

PMID: 23748343

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Project description:Ichthyoses, including inherited disorders of lipid metabolism, display a permeability barrier abnormality in which the severity of the clinical phenotype parallels the prominence of the barrier defect. The pathogenesis of the cutaneous phenotype represents the consequences of the mutation for epidermal function, coupled with a "best attempt" by affected epidermis to generate a competent barrier in a terrestrial environment. A compromised barrier in normal epidermis triggers a vigorous set of metabolic responses that rapidly normalizes function, but ichthyotic epidermis, which is inherently compromised, only partially succeeds in this effort. Unraveling mechanisms that account for barrier dysfunction in the ichthyoses has identified multiple, subcellular, and biochemical processes that contribute to the clinical phenotype. Current treatment of the ichthyoses remains largely symptomatic: directed toward reducing scale or corrective gene therapy. Reducing scale is often minimally effective. Gene therapy is impeded by multiple pitfalls, including difficulties in transcutaneous drug delivery, high costs, and discomfort of injections. We have begun to use information about disease pathogenesis to identify novel, pathogenesis-based therapeutic strategies for the ichthyoses. The clinical phenotype often reflects not only a deficiency of pathway end product due to reduced-function mutations in key synthetic enzymes but often also accumulation of proximal, potentially toxic metabolites. As a result, depending upon the identified pathomechanism(s) for each disorder, the accompanying ichthyosis can be treated by topical provision of pathway product (eg, cholesterol), with or without a proximal enzyme inhibitor (eg, simvastatin), to block metabolite production. Among the disorders of distal cholesterol metabolism, the cutaneous phenotype in Congenital Hemidysplasia with Ichthyosiform Erythroderma and Limb Defects (CHILD syndrome) and X-linked ichthyosis reflect metabolite accumulation and deficiency of pathway product (ie, cholesterol). We validated this therapeutic approach in two CHILD syndrome patients who failed to improve with topical cholesterol alone, but cleared with dual treatment with cholesterol plus lovastatin. In theory, the ichthyoses in other inherited lipid metabolic disorders could be treated analogously. This pathogenesis (pathway)-driven approach possesses several inherent advantages: (1) it is mechanism-specific for each disorder; (2) it is inherently safe, because natural lipids and/or approved drugs often are utilized; and (3) it should be inexpensive, and therefore it could be used widely in the developing world.

Dataset Information

Fortifying the barrier: the impact of lipid A remodelling on bacterial pathogenesis.

Publications

Fortifying the barrier: the impact of lipid A remodelling on bacterial pathogenesis.

Similar Datasets

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