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Regulation of interactions of Gram-negative bacterial endotoxins with mammalian cells

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Abstract

Host defense against many invading Gram-negative bacteria (GNB) depends on innate immune recognition of endotoxin (lipopolysaccharides, LPS), unique surface glycolipids of GNB. Host responses to endotoxin must be highly sensitive but self-limited. In mammals, optimal sensitivity is achieved by ordered interactions of endotoxin with several different extracellular and cell surface proteins—the LPS-binding protein (LBP), CD14, MD-2, and Toll-like receptor (TLR) 4—reflecting the requirement for specific protein–endotoxin and protein–protein interactions. This complex reaction pathway also provides many ways to attenuate endotoxin-driven inflammation and can explain how differences in endotoxin structure, either intrinsic among GNB or induced by metabolic remodeling, can alter host responsiveness and thus the outcome of host-GNB interactions. Major goals of our research are to better understand: (1) the structural bases of specific host-endotoxin interactions; (2) functional diversity among host endotoxin-binding proteins; and (3) how the actions of various endotoxin-binding proteins are regulated to permit optimal host responses to GNB infection. In addition, the identification of a water-soluble endotoxin:MD-2 complex that, depending on the structure of endotoxin or MD-2, has potent TLR4 agonist or antagonist properties suggests novel pharmacologic approaches to immuno-modulation.

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Acknowledgments

We are indebted to the contributions and insights of Athmane Teghanemt, DeSheng Zhang, Polonca Prohinar, Deborah Post, Brad Gibson, Hong Peng Jia Paul McCray, Suzana Hadina, Peter Thorne, Nicole Iovine, Janet Hume, and Hendrik Schultz. Portions of the work reviewed here were supported by United States Public Health Service Grants PO144642 and AI59372 (to J.P.W.) and a Veterans’ Affairs Merit Review Grant (to T.L.G.).

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Authors and Affiliations

  1. The Inflammation Program, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, 2501 Crosspark Rd, Coralville, Iowa City, IA, 52241, USA

    Theresa L. Gioannini & Jerrold P. Weiss

  2. Department of Internal Medicine, Roy J. and Lucille A Carver College of Medicine, University of Iowa, Iowa City, IA, 52242, USA

    Theresa L. Gioannini & Jerrold P. Weiss

  3. Department of Microbiology, Roy J. and Lucille A Carver College of Medicine, University of Iowa, Iowa City, IA, 52242, USA

    Jerrold P. Weiss

  4. Department of Biochemistry, Roy J. and Lucille A Carver College of Medicine, University of Iowa, Iowa City, IA, 52242, USA

    Theresa L. Gioannini

  5. The Immunology Interdisciplinary Program, Roy J. and Lucille A Carver College of Medicine, University of Iowa, Iowa City, IA, 52242, USA

    Jerrold P. Weiss

  6. The Veterans Administration Medical Center, Iowa City, IA, 52246, USA

    Theresa L. Gioannini & Jerrold P. Weiss

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  1. Theresa L. Gioannini
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Correspondence to Jerrold P. Weiss.

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Gioannini, T.L., Weiss, J.P. Regulation of interactions of Gram-negative bacterial endotoxins with mammalian cells. Immunol Res 39, 249–260 (2007). https://doi.org/10.1007/s12026-007-0069-0

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