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DOI: 10.1055/s-0029-1208066
© Georg Thieme Verlag KG Stuttgart · New York
Lymphostatin – ein Multitalent
Multitalented lymphostatinPublication History
eingereicht: 26.8.2008
akzeptiert: 15.1.2009
Publication Date:
17 February 2009 (online)
![](https://www.thieme-connect.de/media/dmw/200909/lookinside/thumbnails/10.1055-s-0029-1208066-1.jpg)
Zusammenfassung
Einleitung: Gastrointestinale Infektionen sind die häufigste Ursache von Durchfallerkrankungen und ein weltweites Problem mit mehr als 1 Milliarde Erkrankungen und ungefähr 3 – 4 Millionen Todesfällen pro Jahr. Gram-negative Bakterien wie Enteropathogene E. coli (EPEC) in Entwicklungsländern und Enterohemorrhagische E. coli (EHEC) in entwickelten Ländern sind für einen Großteil akuter Durchfallerkrankungen, besonders bei Kindern unter 3 Jahren, verantwortlich. Pathogenen E.-coli-Stämmen steht ein Arsenal von Effektorproteinen zur Verfügung, mit denen spezifische Zellfunktionen des Wirts modifiziert und neutralisiert werden können.
Methode: Basierend auf eigenen und einschlägig publizierten Daten erfolgt eine selektive Übersicht zu virulenten Funktionen Gram-negativer Bakterien unter besonderer Berücksichtigung von Lymphostatin.
Ergebnisse: Eines dieser Effektorproteine ist Lymphostatin, kodiert von lifA/efa-1 (lymphocyte inhibitory factor A/ EHEC factor for adherence). lifA/efa-1 und homloge Gene wurden nicht nur in EPEC und EHEC identifiziert, sondern auch in dem Maus-pathogenen Erreger Citrobacter rodentium und verschiedenen Chlamydia-Stämmen. Mehrere Forschungsgruppen haben gezeigt, dass in EHEC-Stämmen lifA/efa-1 Bestandteil eines Pathogenitätskomplexes und somit für eine erhöhte Virulenz verantwortlich ist. Eine DNA- Microarray-Analyse assozierte lifA/efa-1 statistisch als das wichtigste Gen im Zusammenhang mit Diarrhoe, ausgelöst von EPEC. Interessanterweise kodiert lifA/efa-1 für 2 kritische enzymatische Aktivitäten, die auch in anderen pathogenen Bakterien vorkommen – eine Glucosyltransferase – in Clostridium und Protease-Aktivität in Yersinia-Stämmen. In-vitro-Studien mit T-Lymphozyten, isoliert aus peripherem Blut und gastrointestinaler Mukosa, identifizierten Lymphostatin als immunsuppressives Effektorprotein. Darüber hinaus reguliert Lymphostatin auch die Barrierefunktion von Epithelkulturen: Aktivierung von kleiner GTPase RhoA und Inhibition von Cdc42 führen zur Demontage von „adherens junctions” bzw. „tight junctions”. Neben einem Effekt auf das Immunsystem und Epithelzellen funktioniert Lymphostatin auch als Adhäsionsfaktor für EPEC und EHEC, ist essenziell für die Kolonisierung von Maus- und Rinderdarm in vivo und reguliert bakterielle Effektorproteine.
Zusammenfassung: Lymphostatin ist ein weit verbreitetes Toxin in Gram-negativen Bakterien mit mutiplen Funktionen: Zelladhäsion, Immunsuppression, Demontage von Epithelbarrierfunktion und intestinale Kolonisierung.
Summary
Introduction: Gastrointestinal infections are a significant cause of diarrhea and a worldwide problem with annually one billion illnesses and 3 to 4 million deaths. Gram negative bacteria like Enteropathogenic E. coli (EPEC) in developing countries and Enterohemorrhagic E. coli (EHEC) in the developed world are responsible for the majority of acute diarrheal episodes, especially among children less than three years of age. Pathogenic E. coli are supplied with an arsenal of effector proteins to modify and neutralize specific cellular functions of the host organism.
Methods: Based on personal and extensively published results we provide a selected overview of Gram negative virulence functions with a focus on lymphostatin.
Results: Lymphostatin is an effector protein encoded by lifA/efa-1 (lymphocyte inhibitory factor A/ EHEC factor for adherence). lifA/efa-1 and homologous genes have been identified in EPEC, EHEC, and mouse pathogen Citrobacter rodentium, as well as various Chlamydia strains. Multiple groups have shown that in various EHEC strains lifA/efa-1 is part of a larger pathogenicity island responsible for increased virulence. Statistically, DNA Microarray analysis associated lifA/efa-1 as the single most imortant gene with diarrhea caused by EPEC. Interestingly, lifA/efa-1 encodes for two critical enzymatic activities that have been identified in other pathogenic bacteria: glucosyltransferase- in Clostridium- and protease activity in Yersinia strains. In vitro studies identified lymphostatin as an effector protein with an immunosuppressive effect on peripheral blood and gastrointestinal mucosa T lymphocytes. Further, lymphostatin regulates the barrier function of epithelial monolayer cultures: activation of small GTPase RhoA and inhibition of Cdc42 lead to disassembly of adherens junctions and tight junctions, respectively. Besides an effect on immune and epithelial barrier function, lymphostatin also functions as an adhesion factor for EPEC and EHEC, is essential for colonization of mouse and calf intestine, and regulates bacterial effector proteins.
Summary: Lymphostatin is a common toxin in Gram negative bacteria with multiple functions: cell adhesion, immunosuppression, disruption of epithelial barrier function, and intestinal colonization.
Schlüsselwörter
lifA/efa-1 - Enteropathogene E. coli (EPEC) - Enterohemorrhagische E. coli (EHEC) - Citrobacter rodentium - Diarrhoe - Adhäsion - Immunsuppression - Epithelbarrierfunktion - Intestinale Kolonisierung
Keywords
lifA/efa-1 - EPEC - EHEC - Citrobacter rodentium - diarrhea - cell adhesion - immunosuppression - epithelial barrier function - intestinale colonisation
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Jan-Michael A. KlapprothM.D.
Division of Digestive Diseases, Department
of Internal Medicine, Emory University School of Medicine
Atlanta, GA30322 (U.S.A.)
Email: jklappr@emory.edu