Preventing acute gut wall damage in infectious diarrhoeas with glycosylated dendrimers

EMBO Molecular Medicine

Ian Teo¹  Steve M. Toms⁵  Benoit Marteyn²  Teresa S. Barata¹  Peter Simpson⁴  Karen A. Johnston⁵  Pamela Schnupf²  Andrea Puhar²  Tracey Bell⁵  Chris Tang³  Mire Zloh⁶  Steve Matthews⁴  Phillip M. Rendle⁵  Philippe J. Sansonetti² 

[1] Departments of Medicine, Infectious Diseases & Immunity, Imperial College London, Hammersmith Hospital, Ducane Road, London, UK;Institut Pasteur, Unité de Pathogénie Microbienne Moléculaire & Unité INSERM 786, Paris, France;Sir William Dunn School of Pathology, South Parks Road, Oxford, UK;Cross-Faculty NMR Centre & Department of Life Sciences, Imperial College London, South Kensington, London, UK;Industrial Research (IRL), Lower Hutt, New Zealand;UCL School of Pharmacy, University College London, London, UK

关键词: dendrimer;    diarrhoea;    infection;    interleukin‐6;    nanobiotechnology;   

DOI  :  10.1002/emmm.201201290

来源: Wiley

【 摘 要 】

Abstract

Intestinal pathogens use the host's excessive inflammatory cytokine response, designed to eliminate dangerous bacteria, to disrupt epithelial gut wall integrity and promote their tissue invasion. We sought to develop a non-antibiotic-based approach to prevent this injury. Molecular docking studies suggested that glycosylated dendrimers block the TLR4-MD-2-LPS complex, and a 13.6 kDa polyamidoamine (PAMAM) dendrimer glucosamine (DG) reduced the induction of human monocyte interleukin (IL)-6 by Gram-negative bacteria. In a rabbit model of shigellosis, PAMAM-DG prevented epithelial gut wall damage and intestinal villous destruction, reduced local IL-6 and IL-8 expression, and minimized bacterial invasion. Computational modelling studies identified a 3.3 kDa polypropyletherimine (PETIM)-DG as the smallest likely bioactive molecule. In human monocytes, high purity PETIM-DG potently inhibited Shigella Lipid A-induced IL-6 expression. In rabbits, PETIM-DG prevented Shigella-induced epithelial gut wall damage, reduced local IL-6 and IL-8 expression, and minimized bacterial invasion. There was no change in β-defensin, IL-10, interferon-β, transforming growth factor-β, CD3 or FoxP3 expression. Small and orally delivered DG could be useful for preventing gut wall tissue damage in a wide spectrum of infectious diarrhoeal diseases.

–>See accompanying article http://dx.doi.org/10.1002/emmm.201201668

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