Cholesterol Lipids of Borrelia burgdorferi Form Lipid Rafts and Are Required for the Bactericidal Activity of a Complement-Independent Antibody

LaRocca, Timothy J.; Crowley, Jameson T.; Cusack, Brian; Pathak, Priyadarshini; Benach, J.; London, Erwin; García-Moncó, Juan Carlos; Benach, Jorge L.

doi:10.1016/j.chom.2010.09.001

Cited by 95 publications

(129 citation statements)

References 56 publications

(55 reference statements)

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“…First, activation of Hk1 may be required for spirochetes to evade killing by noxious substances generated during digestion of the blood meal and/or elaborated by the midgut epithelium (21,50,74). Based on the near-complete destruction of Hk1-deficient organisms within fed ticks, we hypothesize that the initial lesion is likely a breach in the spirochete's fragile outer membrane that exposes the underlying cell envelope (4,8,43). Our observation that prolonged incubation of hk1 mutants with 72-h-fed nymphal midguts ex vivo did not replicate the killing observed within feeding nymphs (data not shown) implies that killing requires proximity to the midgut epithelium.…”

Section: Discussionmentioning

confidence: 99%

The Hybrid Histidine Kinase Hk1 Is Part of a Two-Component System That Is Essential for Survival of Borrelia burgdorferi in Feeding Ixodes scapularis Ticks

et al. 2011

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Two-component systems (TCS) are principal mechanisms by which bacteria adapt to their surroundings.Borrelia burgdorferi encodes only two TCS. One is comprised of a histidine kinase, Hk2, and the response regulator Rrp2. While the contribution of Hk2 remains unclear, Rrp2 is part of a regulatory pathway involving the spirochete's alternate sigma factors, RpoN and RpoS. Genes within the Rrp2/RpoN/RpoS regulon function to promote tick transmission and early infection. The other TCS consists of a hybrid histidine kinase, Hk1, and the response regulator Rrp1. Hk1 is composed of two periplasmic sensor domains (D1 and D2), followed by conserved cytoplasmic histidine kinase core, REC, and Hpt domains. In addition to its REC domain, Rrp1 contains a GGDEF motif characteristic of diguanylate cyclases. To investigate the role of Hk1 during the enzootic cycle, we inactivated this gene in two virulent backgrounds. Extensive characterization of the resulting mutants revealed a dramatic phenotype whereby Hk1-deficient spirochetes are virulent in mice and able to migrate out of the bite site during feeding but are killed within the midgut following acquisition. We hypothesize that the phosphorelay between Hk1 and Rrp1 is initiated by the binding of feeding-specific ligand(s) to Hk1 sensor domain D1 and/or D2. Once activated, Rrp1 directs the synthesis of cyclic dimeric GMP (c-di-GMP), which, in turn, modulates the expression and/or activity of gene products required for survival within feeding ticks. In contrast to the Rrp2/RpoN/RpoS pathway, which is active only within feeding nymphs, the Hk1/Rrp1 TCS is essential for survival during both larval and nymphal blood meals.

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Section: Discussionmentioning

confidence: 99%

The Hybrid Histidine Kinase Hk1 Is Part of a Two-Component System That Is Essential for Survival of Borrelia burgdorferi in Feeding Ixodes scapularis Ticks

et al. 2011

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“…Cholesterol can remain free in the membrane or can be internalized and glycosylated by undetermined enzymes (22). Subsequently, cholesterol glycolipids are exported to the membrane, where they form lipid rafts (23,24) that are cholesterol-rich domains with a selective presence of lipoproteins (25). The borreliae require cholesterol for growth and have to recruit it from the host because they cannot synthesize it.…”

mentioning

confidence: 99%

Hypercholesterolemia and ApoE deficiency result in severe infection with Lyme disease and relapsing-fever Borrelia

Toledo¹,

Monzón²,

Coleman

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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The Lyme disease (Borrelia burgdorferi) and relapsing-fever (Borrelia hispanica) agents have distinct infection courses, but both require cholesterol for growth. They acquire cholesterol from the environment and process it to form cholesterol glycolipids that are incorporated onto their membranes. To determine whether higher levels of serum cholesterol could enhance the organ burdens of B. burgdorferi and the spirochetemia of B. hispanica in laboratory mice, apolipoprotein E (apoE)-deficient and low-density lipoprotein receptor (LDLR)-deficient mice that produce large amounts of serum cholesterol were infected with both spirochetes. Both apoE-and LDLR-deficient mice infected with B. burgdorferi had an increased number of spirochetes in the joints and inflamed ankles compared with the infected wild-type (WT) mice, suggesting that mutations in cholesterol transport that result in high serum cholesterol levels can affect the pathogenicity of B. burgdorferi. In contrast, elevated serum cholesterol did not lead to an increase in the spirochetemia of B. hispanica. In the LDLR-deficient mice, the course of infection was indistinguishable from the WT mice. However, infection of apoE-deficient mice with B. hispanica resulted in a longer spirochetemia and increased mortality. Together, these results argue for the apoE deficiency, and not hypercholesterolemia, as the cause for the increased severity with B. hispanica. Serum hyperlipidemias are common human diseases that could be a risk factor for increased severity in Lyme disease.cholesterol | Lyme disease | relapsing fever | Borrelia | tick-borne C holesterol is an essential structural component of the cell membrane of vertebrate animals, and it is required for membrane integrity and fluidity. In addition to being a component of the membrane, cholesterol is the precursor of steroid hormones and bile. In eukaryotic cells, cholesterol and sphingolipids are the main components of membrane microdomains known as lipid rafts. These microdomains are characterized as being more tightly packed than the surrounding bilayer and enriched with proteins involved in signaling (1-3).In the bloodstream of humans and other vertebrates, cholesterol is transported in lipoprotein complexes. Apolipoprotein E (apoE) binds cholesterol for transport through the circulatory system as apoE-containing chylomicrons and very-low-density lipoprotein (VLDL) particles. These apoE-cholesterol particles are internalized through the interaction with the low-density lipoprotein receptors (LDLRs). LDLR is one of the cell-surface receptors in cells that binds to apoE to clear the lipoprotein particles from the blood (4). Both apoE-deficient (apoE − ) and LDLR-deficient (LDLR − ) mice show elevated serum cholesterol levels and develop atherosclerotic plaques (5, 6). These mice are the most used mouse models for hyperlipidemia and atherosclerosis research.Lyme disease and relapsing-fever Borrelia have very distinct infection courses and niches in the host. In experimental mouse infections, relapsing-fever borre...

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“…What is less clear is which Borrelia lipids participate in raft formation, and whether the principles of lipid participation in raft formation are similar in bacteria and eukaryotes. Triton X-100 solubilized PC, PG, and MGalD, whereas ACGal, CGal, and free cholesterol were found predominantly in the DRM fraction (33). This suggests that the latter lipids participate in raft formation.…”

Section: Introductionmentioning

confidence: 87%

“…The whole Borrelia lipid extracts and individual Borrelia lipids have various abilities to exist in an ordered state, as assayed by fluorescence anisotropy Previous studies have shown that raft-like ordered lipid microdomains exist in B. burgdorferi membranes in vitro and in vivo (33). To understand the molecular origin of lipid raft formation, the properties of model membrane vesicles composed of various mixtures of B. burgdorferi lipids, as well as those of isolated lipids, were studied.…”

Section: Resultsmentioning

confidence: 99%

“…Lipid microdomains were directly observed by transmission electron microscope (TEM) studies both in lab-cultured B. burgdorferi and B. burgdorferi from infected mice (33), and their proteome was characterized (34). In model membrane vesicles composed of B. burgdorferi whole lipid extracts, co-existing ordered and disordered domains were detected by fluorescence resonance energy transfer (FRET) and a high level of membrane order by 1,6-diphenyl-1,3,5-hexatriene (DPH) fluorescence anisotropy (33). Ordered domains are often detergent resistant (7), so isolation of detergent-resistant membrane (DRM) from B. burgdorferi also supported the hypothesis that they form lipid rafts (33).…”

Section: Introductionmentioning

confidence: 99%

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Ordered Membrane Domain-Forming Properties of the Lipids of Borrelia burgdorferi

Huang

Toledo

Benach

et al. 2016

Biophysical Journal

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Co-existing disordered and ordered (raft) membrane domains exist in Borrelia burgdorferi, the causative agent of Lyme disease. However, although B. burgdorferi contains cholesterol lipids, it lacks sphingolipids-a crucial component of rafts in eukaryotes. To define the principles of ordered lipid domain formation in Borrelia, the domain forming properties of vesicles composed of its three major lipids, acylated cholesteryl galactoside (ACGal), monogalactosyl diacyglycerol (MGalD), and phosphatidylcholine (PC) and/or their mixtures were studied. Anisotropy and fluorescence resonance energy transfer measurements were used to assay membrane order and ordered-domain formation. ACGal had the highest potential to form ordered domains. Interestingly, mixtures of ACGal with B. burgdorferi PC formed ordered domains more readily than mixtures of ACGal with MGalD. This appears to reflect the relatively high level of saturation observed for B. burgdorferi PC, as vesicles containing ACGal and PC, but in which the unsaturated lipid dioleoyl PC was substituted for Borrelia PC, failed to form ordered domains. In addition, the properties of ACGal were compared to those of cholesterol. Depending on what other lipids were present, ordered-domain formation in the presence of ACGal was greater than or equal to that in the presence of cholesterol. Giant unilamellar vesicles formed from ACGal-containing mixtures showed rounded domain shapes similar to those in analogous vesicles containing cholesterol, indicative of liquid-ordered state rather than solid-like gel-state domain formation. Over all, principles of ordered-domain formation in B. burgdorferi appear to be very similar to those in eukaryotes, with saturated PC taking the place of sphingolipids, but with ACGal being the main lipid component inducing ordered-domain formation.

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Cholesterol Lipids of Borrelia burgdorferi Form Lipid Rafts and Are Required for the Bactericidal Activity of a Complement-Independent Antibody

Cited by 95 publications

References 56 publications

The Hybrid Histidine Kinase Hk1 Is Part of a Two-Component System That Is Essential for Survival of Borrelia burgdorferi in Feeding Ixodes scapularis Ticks

The Hybrid Histidine Kinase Hk1 Is Part of a Two-Component System That Is Essential for Survival of Borrelia burgdorferi in Feeding Ixodes scapularis Ticks

Hypercholesterolemia and ApoE deficiency result in severe infection with Lyme disease and relapsing-fever Borrelia

Ordered Membrane Domain-Forming Properties of the Lipids of Borrelia burgdorferi

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