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Polymorphisms on Signaling Lipid a Acylation State and TLR4

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Polymorphisms on Signaling Lipid a Acylation State and TLR4 Differential Activation of Human TLR4 by Escherichia coli and Shigella flexneri 2a Lipopolysaccharide: Combined Effects of Lipid A Acylation State and TLR4 This information is current as Polymorphisms on Signaling of October 5, 2021. Prasad Rallabhandi, Agnes Awomoyi, Karen E. Thomas, Armelle Phalipon, Yukari Fujimoto, Koichi Fukase, Shoichi Kusumoto, Nilofer Qureshi, Marcelo B. Sztein and Stefanie N. Vogel Downloaded from J Immunol 2008; 180:1139-1147; ; doi: 10.4049/jimmunol.180.2.1139 http://www.jimmunol.org/content/180/2/1139 http://www.jimmunol.org/ References This article cites 46 articles, 19 of which you can access for free at: http://www.jimmunol.org/content/180/2/1139.full#ref-list-1 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision by guest on October 5, 2021 • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2008 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Differential Activation of Human TLR4 by Escherichia coli and Shigella flexneri 2a Lipopolysaccharide: Combined Effects of Lipid A Acylation State and TLR4 Polymorphisms on Signaling1 Prasad Rallabhandi,2* Agnes Awomoyi,2* Karen E. Thomas,* Armelle Phalipon,‡ Yukari Fujimoto,§ Koichi Fukase,§ Shoichi Kusumoto,§ Nilofer Qureshi,¶ Marcelo B. Sztein,3† and Stefanie N. Vogel3,4* The lipid A of LPS activates TLR4 through an interaction with myeloid differentiation protein-2 (MD-2) and the degree of lipid A acylation affects TLR4 responsiveness. Two TLR4 single nucleotide polymorphisms (Asp299Gly and Thr399Ile) have been Downloaded from associated with LPS hyporesponsiveness. We hypothesized that the combination of hypoacylation and these single nucleotide polymorphisms would exhibit a compounded effect on TLR4 signaling. HEK293T transfectants expressing wild-type or polymor- phic TLR4 were stimulated with Escherichia coli (predominantly hexaacylated lipid A) or Shigella flexneri 2a (a mixture of hexaacylated, pentaacylated, and predominantly tetraacylated lipid A) LPS, or hexaacylated vs pentaacylated synthetic lipid As. NF-␬B-reporter activity was significantly lower in response to S. flexneri 2a than E. coli LPS and further decreased in polymorphic transfectants. Neither hexaacylated nor pentaacylated synthetic lipid A induced NF-␬B activity in wild-type transfectants under http://www.jimmunol.org/ the identical transfection conditions used for LPS; however, increasing human MD-2 expression rescued responsiveness to hexaacylated lipid A only, while murine MD-2 was required to elicit a response to pentaacylated lipid A. Adherent PBMC of healthy volunteers were also compared for LPS-induced TNF-␣, IL-6, IL-1␤, and IL-10 production. Cytokine levels were signif- icantly lower (ϳ20–90%) in response to S. flexneri than to E. coli LPS/lipid A and PBMC from polymorphic individuals secreted decreased cytokine levels in response to both LPS types and failed to respond to pentaacylated lipid A. Thus, the combination of acylation state and host genetics may significantly impact vaccine immunogenicity and/or efficacy, whether LPS is an integral component of a whole organism vaccine or included as an adjuvant. The Journal of Immunology, 2008, 180: 1139–1147. n response to infection, the capacity of the host to mount an side chain (which confers serologic specificity to the organism), a by guest on October 5, 2021 effective, early innate immune response is a key determinant more conserved “core” oligosaccharide that, in turn, is covalently I of disease resistance or susceptibility. The outer membrane linked to a hydrophobic glycolipid portion, lipid A. Lipid A is of Gram-negative bacteria is comprised predominantly of endo- responsible for the biological activity of LPS and has been termed toxic LPS. LPS elicits a wide variety of biological activities in the the “endotoxic principle” of LPS (4). Proinflammatory signal ini- host (1). For most LPS species, TLR4 acts as the “pattern recog- tiation by LPS depends upon the interaction of the TLR4 receptor nition receptor” that senses LPS, and initiates intracellular signal- complex (i.e., TLR4, MD-2, and CD14) with the lipid A moiety of ing leading to an inflammatory response (2, 3). LPS is comprised LPS. Structural variations within lipid A, such as the number and of three covalently linked regions: a repeating O-polysaccharide positions of acyl chains or the number and position of charged groups on the sugar backbone of the lipid A molecule, greatly influence this interaction (5). Using infrared attenuated total re- *Department of Microbiology and Immunology and †Center for Vaccine Develop- ment, University of Maryland, Baltimore, MD 21201; ‡Institute Pasteur, Paris, flectance spectroscopy, Seydel et al. (6) showed that the endotoxic France; §Osaka University, Osaka, Japan; and ¶Department of Basic Medical Science, effect of lipid A portion of LPS directly correlated with, and School of Medicine, University of Missouri, Kansas City, MO 64108 strongly depends upon, the tilt angle of the sugar backbone with Received for publication March 7, 2007. Accepted for publication November respect to the membrane surface, and the number and distribution 12, 2007. of the hydrocarbon chains. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance It also has been shown that only those LPS molecules comprised with 18 U.S.C. Section 1734 solely to indicate this fact. of a hexaacylated lipid A moiety with a conical/concave shape are 1 This work was supported, in part, with federal funds from National Institute of highly active biologically (5, 6). In contrast, lipid A molecules that Allergy and Infectious Diseases, National Institutes of Health, Department of Health are either tetraacylated or pentaacylated exhibit a cylindrical mo- and Human Services, under Contract No. N01-AI-30028 (to M.B.S.) and Grants AI057927 (to M.B.S.), AI18797 (to S.N.V.), and GM50870 (to N.Q.). lecular shape and greatly attenuated endotoxic activity, and may 2 P.R. and A.A. contributed equally to this study. even exhibit antagonistic activity (6, 7). For example, Hajjar et al. 3 M.B.S. and S.N.V. contributed equally to the direction of this work. (8) found that a hexaacylated Pseudomonas aeruginosa LPS was much more stimulatory in cells expressing human TLR4 than pen- 4 Address correspondence and reprint requests to Dr. Stefanie N. Vogel, Department of Microbiology and Immunology, University of Maryland, 660 West Redwood taacylated LPS prepared from a laboratory strain. Therefore, in Street, Room 324, Baltimore, MD 21201. E-mail address: svogel@som. response to a Gram-negative bacterial infection or vaccine, or in umaryland.edu response to a vaccine in which a TLR4 agonist is present as an Copyright © 2008 by The American Association of Immunologists, Inc. 0022-1767/08/$2.00 adjuvant, the relative contribution of TLR4-mediated signaling to www.jimmunol.org 1140 LPS ACYLATION STATE AND TLR4 SNPs ALTER LPS RESPONSIVENESS the initial host innate immune response may differ depending on their capacity to elicit TLR4-mediated responses, first in a tran- the acylation state of the TLR4 agonist. The induction of a proin- sient transfection system in HEK293T cells (3), and then in flammatory cytokine milieu and up-regulation of costimulatory human PBMC derived from WT (nonpolymorphic) and poly- molecules induced by LPS activation of TLR4 impacts greatly on morphic individuals. The rationale for using Shigella flexneri 2a the subsequent acquired immune response. In this context, struc- was based on the facts that 1) S. flexneri 2a is the single most tural variations such as the degree of acylation within the lipid A important S. flexneri subserotype that causes shigellosis in de- moiety could contribute significantly toward determining the im- veloping countries, and 2) attenuated S. flexneri 2a vaccines are munogenicity and/or efficacy of a specific Gram-negative vaccine. at an advanced stage of development and currently being eval- It has been previously shown that the Escherichia coli LPS is uated in clinical trials (15). In contrast to a previous report (9), comprised mainly of hexaacylated lipid A, whereas Shigella flex- we demonstrate that the S. flexneri 2a LPS used in this study is neri LPS has been reported to be predominantly pentaacylated (9). comprised of a mixture of hexaacylated, pentaacylated, and pre- Therefore, it would be anticipated that the overall TLR4 response dominantly tetraacylated lipid A-containing LPS species. The to S. flexneri 2a LPS would be less than that of cells stimulated lipid A acylation state for the S. flexneri 2a strain used in this with E. coli LPS. study differs from the WT S. flexneri serotype 5a that expressed Just as there are variations in the microbial structures that mainly hexaacylated lipid A-containing LPS species, as re- contribute to the host response, the innate immune response is ported by D’Hauteville et al. (16). Consistent with previous also subject to genetic regulation. TLR4 is a highly conserved observations, S. flexneri 2a LPS elicited significantly dimin- transmembrane receptor for LPS. Arbour et al. (10) identified ished TLR4-mediated signaling when compared with E. coli two TLR4 single nucleotide polymorphisms (SNPs)5 that en- LPS (shown to possess predominantly hexaacylated lipid A- code single amino acid substitutions, Asp299Gly (D299G) and containing LPS), and the response to both LPS preparations was Downloaded from Thr399Ile (T399I), in the ectodomain of human TLR4.
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