The following article was communicated by Carol Lauzon, 17 December 2004. It deals with a symbiotic control delivery of agents to counteract intestinal inflammation.
Copyright © 2004 Federation of European Microbiological Societies Published by Elsevier B.V.
Intestinal immunity of Escherichia coli NISSLE 1917: a safe carrier for therapeutic molecules
Astrid M. Westendorfa, Florian Gunzerb, Stefanie Deppenmeierc, Damini Tapadard, J. Katrin Hungere, M. Alexander Schmidtd, Jan Buera, b, , and Dunja Brudera
FEMS Immunology and Medical Microbiology 10: 023
aArbeitsgruppe Mukosale Immunität, Gesellschaft für Biotechnologische Forschung, Mascheroder Weg 1, D-38124 Braunschweig, Germany
bInstitut für Medizinische Mikrobiologie, Medizinische Hochschule Hannover, Germany
cInstitut für Pathologie, Tierärztliche Hochschule Hannover, Germany
dInstitut für Infektiologie – Zentrum für Molekularbiologie der Entzündung, Westfälische Wilhelms-Universität, Münster, Germany
eAbteilung für Hämatologie und Onkologie, Medizinische Hochschule Hannover, Germany
Received 1 December 2003; revised 25 May 2004; accepted 6 October 2004. Available online 30 November 2004.
The development of novel approaches that allow accurate targeting of therapeutics to the intestinal mucosa is a major task in the research on intestinal inflammation. For the first time, a live genetically modified bacterial strain has been approved by Dutch authorities as a therapeutic agent for experimental therapy of intestinal bowel disease (IBD) in humans. Genetically modified probiotics can very well be used as carriers for localized antigen delivery into the intestine. Therapeutic safety, however, of such a carrier organism, is crucial, especially when a specific probiotic strain has to be used under diseased conditions. In this study, we tested the potential of Escherichia coli NISSLE 1917 to serve as a safe carrier for targeted delivery of recombinant proteins to the intestinal mucosa. In a well-defined and very sensitive immunological system, we demonstrate that intestinal recombinant E. coli NISSLE 1917 has no effect on migration, clonal expansion and activation status of specific CD4+ T cells, neither in healthy mice nor in animals with acute colitis. Furthermore, recombinant E. coli NISSLE 1917 has no effect on the induction or breakdown of peripheral T-cell tolerance in an autoimmune environment. The excellent colonization properties of E. coli NISSLE 1917 render this strain an ideal candidate as carrier organism for gut-focused in situ synthesis of therapeutic molecules.
Keywords: Escherichia coli NISSLE 1917; Localized molecule delivery; T cell response; Immune modulation
Corresponding author. Tel.: +49 531 6181 306; fax: +49 531 6181 748
Unraveling Gut Inflammation
Our intestinal mucosa, particularly that lining the large bowel and terminal ileum, is in constant contact with a resident microflora that is both luxuriant and complex: It consists of some 100 trillion discrete prokaryotic cells comprising an astonishing variety of Gram-positive and Gramnegative facultative aerobic and anaerobic organisms (1). Under normal circumstances, the presence of this vast biotic mass is useful and benign in that it helps prevent colonization of the bowel by pathogens and does not in itself evoke inflammatory immune responses (the normal mucosal immune system is tolerant of its many antigens). Nevertheless, this flora can also cause disease, because there is now good evidence that excessive mucosal immune responses to components of the microflora, either due to abnormal or impaired effector or regulatory (suppressor) cell activity of the host, is the prime cause of inflammatory bowel disease (IBD) (2). One way by which cells in the intestinal milieu may prevent this possible outcome is to apply a number of checks on the resident microflora that control its overall size and composition. On page 1126 of this issue, Cash et al. (3) characterize one such check–the ability of epithelial cells lining parts of the mucosa to produce RegIII (regenerating islet 3 gamma), a C-type lectin with bactericidal properties. This substance may not only regulate the mix of intestinal organisms, but may also eliminate potential pathogens that cannot be controlled by the microflora alone.
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The author is in the Laboratory of Host Defenses, National Institutes of Health. Bethesda, MD 20892-1890. USA. Email: email@example.com .
Symbiotic Bacteria Direct Expression of an Intestinal Bactericidal Lectin
Heather L. Cash,1* Cecilia V. Whitham,1* Cassie L. Behrendt,1 Lora V. Hooper1,2
The mammalian intestine harbors complex societies of beneficial bacteria that are maintained in the lumen with minimal penetration of mucosal surfaces. Microbial colonization of germ-free mice triggers epithelial expression of RegIII, a secreted C-type lectin. RegIII binds intestinal bacteria but lacks the complement recruitment domains present in other microbe-binding mammalian C-type lectins. We show that RegIII and its human counterpart, HIP/PAP, are directly antimicrobial proteins that bind their bacterial targets via interactions with peptidoglycan carbohydrate. We propose that these proteins represent an evolutionarily primitive form of lectin-mediated innate immunity, and that they reveal intestinal strategies for maintaining symbiotic host-microbial relationships.
1 Center for Immunology, The University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA.
2 Department of Microbiology, The University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA.
* These authors contributed equally to this work.
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