Reviewing and identifying amino acids of human, murine, canine and equine TLR4 / MD-2 receptor complexes conferring endotoxic innate immunity activation by LPS/lipid A, or antagonistic effects by Eritoran, in contrast to species-dependent modulation by lipid IVa

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Abstract

There is literature evidence gathered throughout the last two decades reflecting unexpected species differences concerning the immune response to lipid IVa which provides the opportunity to gain more detailed insight by the molecular modeling approach described in this study. Lipid IVa is a tetra-acylated precursor of lipid A in the biosynthesis of lipopolysaccharide (LPS) in Gram-negative bacteria. Lipid A of the prototypic E. coli-type is a hexa-acylated structure that acts as an agonist in all tested mammalian species by innate immunorecognition via the Toll-like receptor 4 (TLR4)/myeloid differentiation factor 2 (MD-2) receptor complex. In contrast, lipid IVa is proinflammatory in mouse cells (agonism) but it remains inactive to human macrophages and even antagonizes the action of potent agonists like E. coli-type lipid A. This particular ambivalent activity profile of lipid IVa has been confirmed in other mammalian species: in equine cells Lipid IVa also acts in a weak agonistic manner, whereas being inactive and antagonizing the lipid A-induced activation of canine TLR4/MD-2. Intriguingly, the respective TLR4 amino acid sequences of the latter species are more identical to the human (67%, 68%) than to the murine (62%, 58%) ortholog. In order to address the unpaired activity-sequence dualism for human, murine, canine and equine species regarding the activity of lipid IVa as compared to LPS and lipid A and, we review the literature and computationally pinpoint the differential biological effects of lipid IVa versus LPS and lipid A to specific amino acid residues. In contrast to lipid IVa the structurally related synthetic compound Eritoran (E5564) acts consistently in an antagonistic manner in these mammalian species and serves as a reference ligand for molecular modeling in this study. The combined evaluation of data sets provided by prior studies and in silico homology mapping of differential residues of TLR4/MD-2 complexes lends detailed insight into the driving forces of the characteristic binding modes of the lipid A domain in LPS and the precursor structure lipid IVa to the receptor complex in individual mammalian species.

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Most cited references 46

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Lipid A modification systems in gram-negative bacteria.

Christian Raetz, C. Reynolds, M. Trent … (2007)

The lipid A moiety of lipopolysaccharide forms the outer monolayer of the outer membrane of most gram-negative bacteria. Escherichia coli lipid A is synthesized on the cytoplasmic surface of the inner membrane by a conserved pathway of nine constitutive enzymes. Following attachment of the core oligosaccharide, nascent core-lipid A is flipped to the outer surface of the inner membrane by the ABC transporter MsbA, where the O-antigen polymer is attached. Diverse covalent modifications of the lipid A moiety may occur during its transit from the outer surface of the inner membrane to the outer membrane. Lipid A modification enzymes are reporters for lipopolysaccharide trafficking within the bacterial envelope. Modification systems are variable and often regulated by environmental conditions. Although not required for growth, the modification enzymes modulate virulence of some gram-negative pathogens. Heterologous expression of lipid A modification enzymes may enable the development of new vaccines.

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Crystal structure of the TLR4-MD-2 complex with bound endotoxin antagonist Eritoran.

Ho Kim, Beom Park, Jung-In Kim … (2007)

TLR4 and MD-2 form a heterodimer that recognizes LPS (lipopolysaccharide) from Gram-negative bacteria. Eritoran is an analog of LPS that antagonizes its activity by binding to the TLR4-MD-2 complex. We determined the structure of the full-length ectodomain of the mouse TLR4 and MD-2 complex. We also produced a series of hybrids of human TLR4 and hagfish VLR and determined their structures with and without bound MD-2 and Eritoran. TLR4 is an atypical member of the LRR family and is composed of N-terminal, central, and C-terminal domains. The beta sheet of the central domain shows unusually small radii and large twist angles. MD-2 binds to the concave surface of the N-terminal and central domains. The interaction with Eritoran is mediated by a hydrophobic internal pocket in MD-2. Based on structural analysis and mutagenesis experiments on MD-2 and TLR4, we propose a model of TLR4-MD-2 dimerization induced by LPS.

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Verónica Mata-Haro, Caglar Cekic, Michael Martin … (2007)

The inflammatory toxicity of lipopolysaccharide (LPS), a component of bacterial cell walls, is driven by the adaptor proteins myeloid differentiation factor 88 (MyD88) and Toll-interleukin 1 receptor domain-containing adapter inducing interferon-beta (TRIF), which together mediate signaling by the endotoxin receptor Toll-like receptor 4 (TLR4). Monophosphoryl lipid A (MPLA) is a low-toxicity derivative of LPS with useful immunostimulatory properties, which is nearing regulatory approval for use as a human vaccine adjuvant. We report here that, in mice, the low toxicity of MPLA's adjuvant function is associated with a bias toward TRIF signaling, which we suggest is likely caused by the active suppression, rather than passive loss, of proinflammatory activity of this LPS derivative. This finding may have important implications for the development of future vaccine adjuvants.

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Author and article information

Journal

Journal ID (nlm-ta): Comput Struct Biotechnol J

Journal ID (iso-abbrev): Comput Struct Biotechnol J

Journal ID (publisher-id): CSBJ

Title: Computational and Structural Biotechnology Journal

Publisher: Research Network of Computational and Structural Biotechnology (RNCSB) Organization

ISSN (Electronic): 2001-0370

Publication date (Electronic): 05 April 2013

Publication date Collection: 2013

Volume: 5

Electronic Location Identifier: e201302012

Affiliations

[a ]Departamento de Farmacia, Benemerita Universidad Autonoma de Puebla, C.P. 72570 Puebla, Pue., Mexico

[b ]Division of Immunochemistry, Research Center Borstel, Leibniz-Center for Medicine and Biosciences, Borstel, Germany

Author notes

Citation

Scior T, Alexander C (2013) Reviewing and identifying amino acids of human, murine, canine and equine TLR4 / MD-2 receptor complexes conferring endotoxic innate immunity activation by LPS/lipid A, or antagonistic effects by Eritoran, in contrast to species-dependent modulation by lipid IVa. Computational and Structural Biotechnology Journal. 5 (6): e201302012. doi: http://dx.doi.org/10.5936/csbj.201302012

[* ] Corresponding author: E-mail address: tscior@ 123456gmail.com (Thomas Scior)

Article

Publisher ID: CSBJ-5-e201302012

DOI: 10.5936/csbj.201302012

PMC ID: 3962135

PubMed ID: 24688705

SO-VID: fc63f9e0-5a8d-47d9-99ec-8e12dea9883c

License:

This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly cited.

History

Date received : 27 October 2012

Date revision received : 12 February 2013

Date accepted : 17 February 2013

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