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Genes and Proteins Underlying Microbial Urinary Tract Virulence Basic Aspects and Applications ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY Editorial Board NATHAN BACK, State University of New York a[.]
Genes and Proteins Underlying Microbial Urinary Tract Virulence Basic Aspects and Applications ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY Editorial Board: NATHAN BACK, State University of New York at Buffalo IRUN R COHEN, The Weizmann Institute of Science DAVID KRITCHEVSKY, Wistar Institute ABEL LAJTHA, N S Kline Institute for Psychiatric Research RODOLFO PAOLETTI, University of Milan Recent Volumes in this Series Volume 475 OXYGEN SENSING: Molecule to Man Edited by Sukhamay Lahiri, Nanduri R Prabhakar, and Robert E Forster, II Volume 476 ANGIOGENESIS: From the Molecular to Integrative Pharmacology Edited by Michael E Maragoudakis Volume 477 CELLULAR PEPTIDASES IN IMMUNE FUNCTIONS AND DISEASES Edited by Jürgen Langner and Siegfried Ansorge Volume 478 SHORT AND LONG TERM EFFECTS OF BREAST FEEDING ON CHILD HEALTH Edited by Berthold Koletzko, Olle Hernell, and Kim Fleischer Michaelsen Volume 479 THE BIOLOGY AND PATHOLOGY OF INNATE IMMUNITY MECHANISMS Edited by Yona Keisari and Itzhak Ofek Volume 480 BIOLOGY OF THE MAMMARY GLAND Edited by Jan A Mol and Roger A Clegg Volume 481 ELASTIC FILAMENTS OF THE CELL Edited by Henk L Granzier and Gerald H Pollack Volume 482 CHROMOGRANINS: Functional and Clinical Aspects Edited by Karen B Helle and Dominique Aunis Volume 483 TAURINE 4: Taurine and Excitable Tissues Edited by Laura Della Corte, Ryan J Huxtable, Giampietro Sgaragli, and Keith F Tipton Volume 484 PHYLOGENETIC PERSPECTIVES ON THE VERTEBRATE IMMUNE SYSTEM Edited by Gregory Beck, Manickam Sugumaran, and Edwin L Cooper Volume 485 GENES AND PROTEINS UNDERLYING MICROBIAL URINARY TRACT VIRULENCE: Basic Aspects and Applications Edited by Levente Emo″dy, Tibor Pál, Jörg Hacker, and Gabriele Blum-Oehler A Continuation Order Plan is available for this series A continuation order will bring delivery of each new volume immediately upon publication, Volumes are billed only upon actual shipment For further information please contact the publisher Genes and Proteins Underlying Microbial Urinary Tract Virulence Basic Aspects and Applications Edited by Levente Emo″dy Tibor Pál University of Pécs Pécs, Hungary and Jörg Hacker Gabriele Blum-Oehler University of Würzburg Würzburg, Germany Kluwer Academic Publishers New York, Boston, Dordrecht, London, Moscow eBook ISBN: Print ISBN: 0-306-46840-9 0-306-46455-1 ©2002 Kluwer Academic Publishers New York, Boston, Dordrecht, London, Moscow All rights reserved No part of this eBook may be reproduced or transmitted in any form or by any means, electronic, mechanical, recording, or otherwise, without written consent from the Publisher Created in the United States of America Visit Kluwer Online at: and Kluwer's eBookstore at: http://www.kluweronline.com http://www.ebooks.kluweronline.com PREFACE Urinary tract infections are among the most frequent diseases caused by microbial pathogens Their clinical manifestations range from uncomplicated episodes to life threatening conditions like urosepsis with septic shock The molecular basis of bacterial mechanisms and host-parasite interactions underlying the pathogenesis of these infections as well as the modern approaches to the diagnosis, therapy and preventive measures have attracted the attention of a wide range of experts A FEMS supported symposium was held on this subject September 16-19, 1999, at Pécs, Hungary The aim of the meeting was to bring together basic researchers, clinical microbiologists and clinicians to exchange the latest ideas covering four major aspects of the main topic, namely: - genetic information, synthesis, and assembly of virulence factors in urinary pathogens regulation of genes involved in the phenotypic appearence of virulence host-parasite interactions determining the process and outcome of the infection possible applications of the above aspects in diagnosis, therapy, and prevention The presentations delivered at this symposium provided the basis for the chapters of this volume The organisers of the conference wish to express their special thanks to the following organisations for their financial support and contribution to the realisation of the symposium: Federation of the European Microbiological Societies (FEMS), German Society for Hygiene and Microbiology (DGHM) and Hungarian Society for Microbiology Levente Emo″dy Tibor Pál Pécs Jörg Hacker Gabriele Blum-Oehler Würzburg v This page intentionally left blank CONTENTS KEYNOTE LECTURES URINARY TRACT INFECTION: FROM BASIC SCIENCE TO CLINICAL APPLICATION Jörg Hacker INNATE DEFENCES AND RESISTANCE TO GRAM NEGATIVE MUCOSAL INFECTION GabrielaGodaly, Göran Bergsten, Björn Frendéus, Long Hang, Maria Hedlund, Diana Karpman, Patrik Samuelsson, Majlis Svensson, GiselaOtto, Björn Wullt, andCatharina Svanborg SESSION I GENETIC INFORMATION, SYNTHESIS, ASSEMBLY, AND ACTIVATION PROCESSES IN VIRULENCE MECHANISMS PATHOGENICITY ISLANDS OF UROPATHOGENIC E COLI AND EVOLUTION OF VIRULENCE Gabriele Blum-Oehler, Ulrich Dobrindt, Britta Janke, Gábor Nagy, Katharine Piechaczek, and Jörg Hacker IRON TRANSPORT IN ESCHERICHIA COLI: Crystal Structure of FhuA, an Outer Membrane Iron and Antibiotic Transporter Volkmar Braun, Michael Braun, and Helmut Killmann THE CYTOTOXIC NECROTIZING FACTOR (CNF1) FROM UROPATHOGENIC ESCHERICHIA COLI Patrice Boquet GENETIC CHARACTERIZATION OF THE UROPATHOGENIC E COLI STRAIN 536 - A SUBTRACTIVE HYBRIDIZATION ANALYSIS Britta Janke, Jörg Hacker, and Gabriele Blum-Oehler 25 33 45 53 vii viii Contents ANALYSIS OF THE HEMOLYSIN DETERMINANTS OF THE UROPATHOGENIC E COLI STRAIN 536 Gábor Nagy, Ulrich Dobrindt, Gabriele Blum-Oehler, Levente Emo″dy, Werner Goebel, and Jörg Hacker FUNCTIONAL VARIABILITY OF TYPE FIMBRIAE OF ESCHERICHIA Riitta Pouttu, Terhi Puustinen, Maini Kukkonen, Ritva Virkola, Minni Laurila, Jörg Hacker, Per Klemm, and Timo K Korhonen 57 63 HPI OF HIGH-VIRULENT YERSINIA IS FOUND IN E COLI STRAINS CAUSING URINARY TRACT INFECTION : Structural, Functional Aspects, and Distribution 69 Sören Schubert, Johanna L Sorsa, Sonja Cuenca, Daniela Fischer, Christoph A Jacobi, and Jürgen Heesemann AGGREGATION SUBSTANCE OF ENTEROCOCCUS FAECALIS : A MULTIFUNCTIONAL ADHESIN Albrecht Muscholl-Silberhorn, Eva Rozdzinski, and Reinhard Wirth 75 SESSION II REGULATION AND EXPRESSION OF VIRULENCE GENES A ROLE FOR THE σs SUBUNIT OF RNA POLYMERASE IN THE REGULATION OF BACTERIAL VIRULENCE 85 Regine Hengge-Aronis TRANSCRIPTIONAL ORGANISATION AND REGULATION OF E COLI GROUP II CAPSULE EXPRESSION 95 Ian S Roberts MOLECULAR BASIS OF CATHETER ASSOCIATED INFECTIONS BY STAPHYLOCOCCI Friedrich Götz, Christine Heilmann, and Sarah E Cramton 103 CONTROL MECHANISMS IN THE PAP-PILI SYSTEM 113 Bernt Eric Uhlin, Carlos Balsalobre, Kristina Forsman-Semb, Mikael Göransson, Jana Jass, Jörgen Johansson, Saule Naureckiene, Berit Sondén, Jurate Urbonaviciene, and Yan Xia Contents TRANSCRIPTIONAL ANALYSIS OF THE SFA AND PAP DETERMINANTS OF UROPATHOGENIC E COLI STRAINS Carlos Balsalobre, Joachim Morschhäuser, Jörg Hacker, and Bernt Eric Uhlin ix 119 STRUCTURAL AND FUNCTIONAL STUDIES OF THE FIMBRIAL ADHESIN GENE REGULATOR PAPB FROM UROPATHOGENIC E COLI 123 Yan Xia, Kristina Forsman-Semb, Jana Jass, and Bernt Eric Uhlin INTERACTION OF THE NUCLEOID-ASSOCIATED PROTEINS HHA AND H-NS TO MODULATE EXPRESSION 127 OF THE HEMOLYSIN OPERON IN E COLI Antonio Juárez, José M Nieto, Antoni Prenafetá, Elisabet Miquelay, Carlos Balsalobre, Montserrat Carrascal, and Cristina Madrid USE OF THE OMPS-DISPLAY – SYSTEM TO LOCALIZE THE RECEPTOR-BINDING REGION IN THE PAPG ADHESIN OF UROPATHOGENIC E COLI Hannu Lång, Minna Mäki, Anssi Rantakari, and Timo K.Korhonen 133 THE ROLE OF THE AirS TWO-COMPONENT SYSTEM IN UROPATHOGENIC E COLI 137 Anna-Karin Pernestig, Staffan J Normark, Dimitris Georgellis, and Öjar Melefors EXAMINATION OF REGULATORY CROSS-TALK BETWEEN THE DECAY ACCELERATING FACTOR-BINDING FIMBRIAL/AFIMBRIAL ADHESINS AND TYPE I FIMBRIAE Nicola Holden, Claire Cotterill, and David Gally 143 MODULATION OF THE POLYSACCHARIDE INTERCELLULAR ADHESIN (PIA) EXPRESSION IN BIOFILM FORMING STAPHYLOCOCCUS EPIDERMIDIS 151 Wilma Ziebuhr, Isabel Lưßner, Shwan Rachid, Katja Dietrich, Friedrich Gưtz, and Jưrg Hacker x Contents INDUCTION OF STAPHYLOCOCCUS EPIDERMIDIS BIOFILM FORMATION BY ENVIRONMENTAL FACTORS: THE POSSIBLE INVOLVEMENT OF THE ALTERNATIVE TRANSCRIPTION FACTOR SIGB 159 Shwan Rachid, Seunghak Cho, Knut Ohlsen, Jörg Hacker, and Wilma Ziebuhr EXPRESSION OF VIRULENCE GENES IN CANDIDA ALBICANS Peter Staib, Marianne Kretschmar, Thomas Nichterlein, Gerwald Köhler, and Joachim Morschhäuser 167 EFFECT OF SPONTANEOUS AND INDUCED MUTATIONS ON OUTER MEMBRANE PROTEINS AND LIPOPOLYSACCHARIDES OF PROTEUS PENNERI STRAIN 357 177 Ildikó Kustos, Vilmos Tóth, Ferenc Kilár, Béla Kocsis, and Levente Emo″dy SESSION III HOST-PARASITE INTERACTIONS ROLE OF BACTERIAL LECTINS IN URINARY TRACT INFECTIONS Itzhak Ofek, David L Hasty, Soman N Abraham, and Nathan Sharon ADHERENCE OF ENTERIC BACTERIA ONTO THE MAMMALIAN EXTRACELLULAR MATRIX Timo K.Korhonen 183 193 INTERRELATIONSHIP BETWEEN VIRULENCE PROPERTIES OF UROPATHOGENIC E COLI AND BLOOD GROUP PHENOTYPE OF PATIENTS WITH CHRONIC URINARY TRACT INFECTION 201 Reinhard Fünfstück, Niels Jacobsohn, and Günter Stein GLYCOLIPID RECEPTORS OF F1C FIMBRIAL ADHESIN OF UROPATHOGENIC E.COLI 213 A Salam Khan and Jörg Hacker xi Contents THIN AGGREGATIVE FIMBRIAE ON URINARY E COLI ISOLATES Eszter Pátri, Edina Szabó, Tibor Pal, and Levente Emo″dy 219 TYPE PILI OF CITROBACTER FREUNDII MEDIATE INVASION INTO HOST CELLS 225 Petra Hess, Neda Daryab, Kai Michaelis, Anita Reisenauer, and Tobias A Oelschlaeger SEROTYPES, SIDEROPHORE SYNTHESIS, AND SERUM RESISTANCE OF UROPATHOGENIC KLEBSIELLA ISOLATES Mine Ang-Kỹỗỹker, ệmer Kỹỗỹkbasmaci, Mehmet Tekin, Didem Akbulut, Özden Büy ükbaba-Boral, and Özdem Ang˘ 237 EPITOPE SPECIFICITY OF POLYCLONAL RABBIT ANTISERA AGAINST PROTEUS VULGARIS O-ANTIGENS 243 Beata Bartodziejska, Agnieszka Torzewska, Dorota Babicka, Marianna Wykrota, Antoni Rózalski, Andrei V Perepelov, Filip V Toukach, and Yuriy A Knirel VIRULENCE FACTORS OF ESCHERICHIA COLI ISOLATED FROM URINE OF DIABETIC WOMEN WITH ASYMPTOMATIC BACTERIURIA 249 Suzanne E Geerlings, Ellen C.Brouwer, Wim Gaastra, and Andy M Hoepelman CYTOKINE SECRETION IS IMPAIRED IN WOMEN WITH DIABETES MELLITUS Suzanne E Geerlings, Ellen C.Brouwer, Kok P M van Kessel, Wim Gaastra, and Andy M Hoepelman 255 CHARACTERISATION AND ADHERENCE MECHANISMS OF ESCHERICHIA COLI STRAINS CAUSING INFECTIONS IN PATIENTS WITH A RECONSTRUCTED BLADDER 263 Sally J Keegan, Carlos E Hormaeche, Jeffery P Pearson, and David L Gally IMMUNODOMINANT PROTEINS IN HUMAN SEPSIS CAUSED BY METHICILLIN RESISTANT STAPHYLOCOCCUS AUREUS Udo Lorenz, Knut Ohlsen, Helge Karch, Arnulf Thiede, and Jörg Hacker 273 xii Contents SESSION IV APPLICATIONS: DIAGNOSIS, THERAPY AND PREVENTION MODERNCONCEPT OFANTIBIOTIC THERAPY OF URINARY TRACT INFECTION Raymond Auckenthaler 279 THE ROLE OFANAEROBIC BACTERIA INPROSTATITIS 289 ElisabethNagy, Ildikó Szo″ke, LaszloTưrưk, andLaszlo Pajor URINARY TRACT INFECTION IN DOGS: Analysis of 419 urocultures carried out in Portugal Constanỗa P Féria, José D Correia, Jorge Machado, Rui Vidal, and JosộGonỗalves DETECTION OF VIRULENCE FACTORS IN UROPATHOGENIC ESCHERICHIA COLI ISOLATED FROM HUMANS, DOGS AND CATS IN PORTUGAL Constanỗa P Fộria, Josộ D Correia, Josộ Gonỗalves, and Jorge Machado 301 305 ASYMPTOMATIC BACTERIURIA CAN BE CONSIDERED A DIABETIC COMPLICATION IN WOMEN WITH DIABETES MELLITUS 309 Suzanne E Geerlings, Ronald P Stolk , Marielle J L Camps, Paetrick M Netten, Joost B L Hoekstra, Paul K Bouter, Bert Braveboer, Theo J Collet, Arjen R Jansz, and Andy M Hoepelman DETERMINATION OF GENETIC DIVERSITY OF PROTEUS PENNERI STRAINS USING REP-PCR Marcin Kowalczyk and Zygmunt Sidorczyk 315 USE OF RANDOMLYAMPLIFIED POLYMORPHIC DNA (RAPD) ANALYSIS FOR IDENTIFICATION OF PROTEUS PENNERI 321 Iwona Kwil, Jaroslaw Dziadek, Dorota Babicka, Aleksandra Cierniewska-Cies´lak, and Antoni Rózalski xiii Contents OVERVIEWONTHE CLINICAL STUDIES WITH UROSTIM IMMUNOSTIMULATOR AGAINST UROGENITAL INFECTIONS 325 Plamen Nenkov PORCINE POSTWEANING DIARRHEA ISOLATES OF E COLI WITH UROPATHOGENIC CHARACTERS István Tóth, Eric Oswald, Jacques Mainil, Mohamed Awad-Masalmeh, and Béla Nagy 331 VIRULENCE MARKERS OF HUMAN UROPATHOGENIC ESCHERICHIA COLI STRAINS ISOLATED IN HUNGARY 335 István Tóth, Eric Oswald, Béla Szabó, István Barcs, and Levente Emo″dy NEW SEROGROUPS OF THE GENUS PROTEUS CONSISTING OF PROTEUS PENNERI STRAINS ONLY Determination of some LPS epitopes responsible for specifity 339 KrystynaZych, Marcin Kowalczyk, Yuriy A Knirel, andZygmunt Sidorczyk THE ROLE OF CHLAMYDIA TRACHOMATIS IN ASYMPTOMATIC AND SYMPTOMATIC UROGENITAL INFECTIONS 345 JudithDeákandElisabethNagy LIST OF CONTRIBUTORS 351 INDEX 363 This page intentionally left blank URINARY TRACT INFECTION: FROM BASIC SCIENCE TO CLINICAL APPLICATION Jörg Hacker lnstitut für Molekulare Infektionsbiologie der Universität Würzburg, Röntgenring 11, D-97070 Würzburg, Tel 0931/31-2575, Fax 0931/31-2578 INTRODUCTION Urinary tract infections (UTIs) represent one of the most important infectious syndroms in countries of the industrialized world In addition to the main uropathogen, Escherichia coli, more and more non-E coli pathogens have been detected as causative agents of UTI Thus, grampositive bacteria (Staphylococci, Enterococci) as well as fungal pathogens ( Candida albicans, Candida glabrata ) are able to cause urinary tract infections especially in elderly persons and hospitalized patients However, for many years, urinary pathogens have been chosen as model organisms to study issues of molecular pathogenesis The genome structure of pathogens, the concept of virulence factors, important features of gene regulation, hostparasite interactions and the role of host factors in infectious diseases have been studied with urinary pathogens This article describes recent developments in the analysis of UTI and future trends, presented during the FEMS Symposium on UTI, held in Pecs (Hungary) in summer 1999 UROPATHOGENIC ORGANISM Urinary tract infections can be divided into complicated and noncomplicated infectious diseases The main pathogen of non-complicated urinary tract infections is Escherichia coli E coli is not only detected in Genes and Proteins Underlying Microbial Urinary Tract Virulence Edited by L Emo″dy et al., Kluwer Academic/Plenum Publishers, 2000 Jörg Hacker urinary tract infections in humans but also plays an important role in UTI of certain animals, especially dogs It is interesting to note that also intestinal pathogens of porcine origin exhibit features of uropathogenic E coli Over the last few years several non-E coli bacteria were identified to be uropathogenic Those bacteria were often found in patients suffering from complicated urinary tract infections, including patients with either catheters or suffering from stone formation or in immunocompromized patients Thus, multiresistant Klebsiella pneumoniae and Pseudomonas aeruginosa as well as certain Proteus species are important of non- E coli uropathogens One has to take in mind that especially the newly established species Proteus penneri seems to be a newly emerging uropathogen2 In addition, grampositive bacteria also play an increasing role as nosocomial pathogens in UTI Thus, the biofilm forming S aureus and S epidermidis species are of particular importance Moreover, Chlamydia trachomatis, Mycoplasma hominis and Ureaplasma urealyticum represent important uropathogens Anaerobic bacteria play an important role especially during prostatitis Fungi (Candida albicans, Candida glabrata) also represent an emerging group of uropathogens, especially in patients following organ transplantation and chemotherapy GENE STRUCTURE OF UROPATHOGENS Studies on the genome structure of uropathogens were performed especially with uropathogenic E coli It is of interest that the complete genome sequence of the non-pathogenic E coli K-12 isolate was established two years ago on the basis of this sequence It became obvious that pathogenic E coli, including uropathogenic organisms, contain additional pieces of DNA, which can be part of plasmids, bacteriophages or may represent particular fragments of the genome, termed pathogenicity islands4 Enterohemorrhagic E coli, another group of intestinal pathogenic E coli bacteria, contain at least one megabase additional DNA compared to E coli K-12 It is suggested that uropathogenic E coli may also carry additional 300 to 400 kb of DNA The analysis of the genome of the uropathogenic E coli strain 536 exhibited four additional pieces of DNA forming pathogenicity islands with a size range from 25 - 190 kb In the future, the application of new techniques, including the representative difference analysis (RDA) and the two-dimensional (2D) protein gel electrophoresis will be of great advantage in the discovery and characterization ofadditional virulence factors which may be part of pathogenicity islands in uropathogenic bacteria Urinary Tract Infection: From Basic Science to Clinical Application VIRULENCE FACTORS Pathogenicity islands carry genes, which encode important virulence factors (see Fig 1), including iron uptake systems5 Figure1 Schematic diagram on the interaction between uropathogenic organism and host cell structures (for details see text) It is of particular importance that yersiniabactin, an iron uptake system, first described for pathogenic Yersinia , is also encoded by the majority of uropathogenic E coli This iron uptake system is located on a conserved pathogenicity island which is present in many enterobacteria In addition, yersiniabactin and the seven iron uptake systems described for the nonpathogenic E coli K-12 organisms, aerobactin is also produced by uropathogenic E coli strains Toxins are important for the pathogenesis of urinary tract infections7 In uropathogenic E coli , the α -hemolysin toxin was described many years ago Recently, an accumulating amount of data concerning the maturation of the α -hemolysin toxin in UPEC, its secretion and the regulation of the corresponding genes appeared In addition, the cytotoxic necrotizing factor I, which is responsible for Rho modification and subsequent activation of small host GTPases has been analyzed A newly identified toxin, the cytolethal destending toxin (CDT), was also found to be Jörg Hacker produced by uropathogenic E coli , its role in the pathogenesis, however, remains to be elucidated Another import feature of pathogenic bacteria are adherence factors The fimbriae from uropathogenic E coli are well described3 It was shown that Pfimbriae, which are able to bind to Gal αl-4 Gal-receptors carry receptor binding molecules, termed PapG, exhibiting the receptor binding domain in their N-terminal parts Recently, the importance of sequence alterations of the major subunit FimA and the minor subunit FimH of mannose-specific type I fimbriae were illustrated by the finding that pathoadaptive mutations are important for the binding capacity of the type I adherence factors Sfimbriae and type I C-fimbriae are also important adherence factors of uropathogenic E coli These adherence factors have the capacity to bind to an asialo GM2 receptor structure It is of great interest whether additional binding factors, especially thin aggregative fimbriae are of importance for the pathogenesis of UTI Other non E coli uropathogenic bacteria also produce important binding molecules This is especially true for the capacity of biofilm formation, which is exhibited by Enterococci and Staphylococci8 In Enterococci the aggregative slime substance is identical to the clumping factor, which plays an important role in DNA transfer via conjugation In S epidermidis and as described recently, also in S aureus, the so-called PIA antigen, a β 1,6 N-Acetyl Glucosamine polymer is important for biofilm formation However, capsules are also important virulence factors of gram-negative uropathogens The flagella seem to play a role in the virulence of Proteus strains9 Proteases are necessary for full virulence of Candida albicans The analysis of the newly established Proteus penneri strains exhibit an array of new important virulence factors, such as IgA proteases and ureases2 With the help of the newly established techniques in molecular biology and on the basis of the emerging genome sequences, new virulence factors will be identified and analyzed within the next few years HOST-PARASITE INTERACTIONS The different virulence factors identified, play a key-role in the interaction of uropathogens with host cell structures (see Fig 1) It is of particular importance that the adherence factors not simply bind to uroepithelial cells, but that the majority of these factors play a role in these interaction of the pathogens with extracellular matrix molecules Thus, the FimH-adhesin has the capacity to interact with laminin In addition, FimA ' Urinary Tract Infection: From Basic Science to Clinical Application may act as a receptor for plasminogen, which in turn leads to plasmin activation and fibrinolysis G-fimbriae bind to type IV collagen and P (Pap)pili have the capacity to interact with fibronectin These interactions, of course, have important consequences for the penetration of the bacteria through the extracellular matrix Therefore, the penetration process has also been termed as ,,bacterial metastasis“ Fimbriae, however, may also be involved in triggering the invasion capacity of uropathogens into eukaryotic cells A gene cluster, similar to type I fimbriae of Salmonella is responsible for the production of proteins, which act as invasion factors of Citrobacter freundii Also other uropathogens, including uropathogenic E coli, have the capacity to invade eukaryotic cells Furthermore, fimbriae are able to trigger the cytokine response of epithelial cells As shown by C Svanborg and co-workers10, Pfimbriae have the capacity to induce the IL-6 response of infected loot cells A particular variant of type I fimbriae is involved in IL-8 expression The expression of the IL-8 receptor molecule is important for the penetration of neutrophiles through the tissue layer It is interesting to note that epithelial cells from patients, suffering from diabetes mellitus show a low level response with respect to cytokine production, compared to cells isolated from healthy persons Also patients with a reconstituted bladder show a different cytokine response to uropathogens compared to a control group The analysis of host factors is extremely important to understand the development of urinary tract infections Thus, the blood group antigen is involved in the binding capacity of uropathogens to host cells via P-fimbriae Future studies, which will include the microarray chip technology will certainly lead to new observations regarding the host response on urinary pathogens Using the chip technology it will be possible to analyse the expression of various host genes, including cytokine specific gene clusters, genetic determinants encoding receptor molecules and gene loci, whose products are involved in cell signalling These data will broaden our knowledge on the host response to urinary tract infections GENE REGULATIONANDPHASEVARIATION Uropathogens, especially uropathogenic E coli were used in the last years as model organism to study the regulation of virulence associated genes11 Fimbriae, flagella, capsules as well as hemolysin determinants were described with respect to the acting gene regulators Activators as well as .. .Genes and Proteins Underlying Microbial Urinary Tract Virulence Basic Aspects and Applications ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY Editorial Board: NATHAN... the publisher Genes and Proteins Underlying Microbial Urinary Tract Virulence Basic Aspects and Applications Edited by Levente Emo″dy Tibor Pál University of Pécs Pécs, Hungary and Jörg Hacker... not only detected in Genes and Proteins Underlying Microbial Urinary Tract Virulence Edited by L Emo″dy et al., Kluwer Academic/Plenum Publishers, 2000 Jörg Hacker urinary tract infections in