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«(Über die Bedeutung der bakteriellen Genomplastizität für die Adaptation und Evolution asymptomatischer Bakteriurie (ABU) Escherichia coli ...»

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Multi locus sequence typing suggested that certain ABU strains evolved from UPEC variants that are able to cause symptomatic UTI by genome reduction. Consequently, the high E. coli genome plasticity does not allow a generalized view on geno- and phenotypes of individual isolates within a clone. Reductive evolution by point mutations, DNA rearrangements and deletions resulted in inactivation of genes coding for several UPEC virulence factors, thus supporting the idea that a reduced bacterial activation of host mucosal inflammation promotes the ABU lifestyle of these E. coli isolates.

Gene regulation and genetic diversity are strategies which enable bacteria to live and survive under continuously changing environmental conditions. To study adaptational changes upon long term growth in the bladder, consecutive re-isolates of model ABU strain 83972 derived from a human colonisation study and from an in vitro long term cultivation experiment were analysed with regard to transcriptional changes and genome rearrangements. In this context, it could be demonstrated that E. coli, when exposed to different host backgrounds, is able to adapt its metabolic networks resulting in an individual bacterial colonisation strategy.

Transcriptome and proteome analyses demonstrated distinct metabolic strategies of nutrients acquisition and energy production of tested in vivo re-isolates of strain 83972 that enabled

12   Summary 

them to colonise their host. Utilisation of D-serine, deoxy- and ribonucleosides, pentose and glucuronate interconversions were main up-regulated pathways providing in vivo re-isolates with extra energy for efficient growth in the urinary bladder. Moreover, this study explored bacterial response networks to host defence mechanisms: The class III alcohol dehydrogenase AdhC, already proven to be involved in nitric oxide detoxification in pathogens like Haemophilus influenzae, was shown for the first time to be employed in defending E. coli against the host response during asymptomatic bacteriuria.

Consecutive in vivo and in vitro re-isolates of strain 83972 were also analysed regarding their genome structure. Several changes in the genome structure of consecutive re-isolates derived from the human colonisation study implied the importance of bacterial interactions with the host during bacterial microevolution. In contrast, the genome structure of re-isolates from the in vitro long term cultivation experiment, where strain 83972 has been propagated without host contact, was not affected. This suggests that exposure to the immune response promotes genome plasticity thus being a driving force for the development of the ABU lifestyle and evolution within the urinary tract.

 

1. Zusammenfassung   Asymptomatische Bakteriurie (ABU) stellt eine bakterielle Infektion der Harnblase über einen langen Zeitraum dar, die häufig von Escherichia coli hervorgerufen wird, ohne dass typische Symptome einer Harnwegsinfektion auftreten. Um die Charakteristika von ABU E. coli Isolaten genauer zu untersuchen, wurden die Geno- und Phänotypen von 11 ABU-Isolaten verglichen. Außerdem wurden in mehreren aufeinanderfolgenden in vivo-Reisolaten des Modell-ABU Stammes 83972 die Veränderungen im Transkriptom, Proteom und Genom während einer langfristigen Persistenz in der menschlichen Blase charakterisiert. Schließlich wurde der Effekt des menschlichen Wirtes auf die bakterielle Adaptation durch einen Vergleich von in vitro- mit in vivo-kultivierten Stämmen abgeschätzt.

ABU-Isolate stellt eine heterogene Gruppe von Organismen dar. Diese können den vier phylogenetischen Hauptgruppen von E. coli sowie unterschiedlichen klonalen Gruppen zugeordnet werden. Dementsprechend unterscheiden sie sich erheblich bezüglich der Zusammensetzung des Genomes, der Genomgröße und auch der Ausstattung mit UPECtypischen Virulenz-assoziierten Genen. Multi-Lokus-Sequenz-Typisierung legt nahe, dass bestimmte ABU Stämme sich durch Genomreduktion aus UPEC Stämmen entwickelt haben, die eine Harnwegsinfektion mit charakteristischen Symptomen auslösen konnten. Folglich erlaubt die hohe Genomplastizität von E. coli keine generalisierte Betrachtung einzelner Isolate eines Klons. Genomreduktion über Punktmutationen, Genom-Reorganisation und Deletionen resultierte in der Inaktivierung einiger Gene, die für einige UPEC VirulenzFaktoren kodieren. Dies stützt die Vorstellung, dass eine verminderte bakterielle Aktivierung der Entzündung der Wirtsschleimhaut den Lebensstil von ABU (bei diesen E. coli-)Isolaten fördert.

Genregulation und genetische Diversität sind Strategien, die es Bakterien ermöglichen unter sich fortlaufend ändernden Bedingungen zu leben bzw. zu überleben. Um die anpassungsbedingten Veränderungen bei einem langfristigen Wachstum in der Blase zu untersuchen, wurden aufeinanderfolgende Reisolate, denen eine langfristige in vivoKolonisierung im menschlichen Wirt beziehungsweise eine in vitro-Kultivierung vorausgegangen ist, im Hinblick auf Veränderungen Genexpression und Genomorganisation analysiert. In diesem Zusammenhang konnte gezeigt werden, dass E. coli in der Lage ist, seine metabolischen Netzwerke verschiedenen Wachstumsbedingungen anzupassen und

14   Zusammenfassung 

individuelle bakterielle Kolonisierungsstrategien entwickeln kann. Transkriptom- und Proteom-Analysen zeigten verschiedene metabolische Strategien zur Nährstoffbeschaffung und Energieproduktion bei untersuchten in vivo-Reisolaten vom Stamm 83972, die es ihnen ermöglichen, den Wirt zu kolonisieren. Das Zurückgreifen auf D-Serin, Deoxy- und Ribonucleoside sowie die bidirektionale Umwandlung zwischen Pentose und Glucuronat waren hoch-regulierte Stoffwechselwege, die die in vivo-Reisolate mit zusätzlicher Energie für ein effizientes Wachstum in der Blase versorgen. Zudem wurden in dieser Studie die Netzwerke für eine Reaktion auf Abwehrmechanismen des Wirtes erforscht: Erstmals wurde hier die Rolle der Klasse-III-Alkoholdehydrogenase AdhC, bekannt durch ihre Bedeutung bei der Entgiftung von Stickstoffmonoxid, bei der Wirtsantwort während einer asymptomatischen Bakteriurie gezeigt.





Aufeinanderfolgende in vivo- und in vitro-Reisolate vom Stamm 83972 wurden ebenfalls bezüglich ihrer Genomstruktur analysiert. Einige Veränderungen in der Genomstruktur der aufeinanderfolgenden Reisolate, die von einer humanen Kolonisierungsstudie stammen, implizieren die Bedeutung einer Interaktion der Bakterien mit dem Wirt bei der Mikroevolution der Bakterien. Dagegen war die Genomstruktur von Reisolaten eines langfristigen in vitro-Kultivierungsexperiments, bei dem sich der Stamm 83972 ohne Wirtskontakt vermehrt hat, nicht von Veränderungen betroffen. Das legt nahe, dass die Immunantwort eine Genomplastizität fördert und somit eine treibende Kraft für den ABU Lebensstil und die Evolution im Harnwegstrakt ist.

         

2. Introduction

2.1. Epidemiology of urinary tract infection   Urinary tract infections (UTIs) are considered to be the most common bacterial infection in industrialized countries. About every third woman might have UTI episode(s) that require antimicrobial therapy by the age of 24 years, and 40 % to 50 % of women will experience at least one UTI during their lifetime (Foxman, 2002). It is estimated, however, that 20 % of all UTIs occur in men and rates are lower in young men and increase dramatically with increasing age (Griebling, 2005).

Patients with a normal genitourinary tract with no prior instrumentation are considered as “uncomplicated” (Stamm and Hooton, 1993). The majority of acute community-acquired, uncomplicated infections are caused by Escherichia coli (70 % to 90 %) or Staphylococcus saprophyticus (10 % to 15 %). Klebsiella, Enterobacter, and Proteus species and enterococci infrequently case uncomplicated cystitis and pyelonephritis (Ronald, 2002). The reservoir for these bacteria is the human bowel flora and most infections result from bacteria introduced into the bladder via the urethra. Sexual activity significantly increases the frequency of uropathogen transmission and UTI incidence (Foxman et al., 2002).

Specific subpopulations are more often prone to UTIs. This group includes infants, pregnant women, the elderly, patients with spinal cord injuries and/or catheters, patients with diabetes, or patients underlying urologic abnormalities (Foxman, 2002). An abnormal urinary tract may lead to colonisation with less virulent organisms that rarely cause disease in the anatomically or metabolically functional one. While in uncomplicated UTIs the most common causative pathogen is Escherichia coli (E. coli), the etiology of complicated UTI is more diverse and frequently polymicrobial in nature (Ronald, 2002). However, E. coli causes about 40 % of all nosocomial UTIs and represents one of the most frequently isolated nosocomial pathogen (Struelens et al., 2004).

UTI can also be classified by the site of infection, as follows: infection of the bladder (cystitis) or the kidneys (pyelonephritis). Bacterial colonisation of the urinary tract is often accompanied by a wide spectrum of symptoms (symptomatic infection) like burning or pain

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during urination, fever, cloudy or bloody urine and increased urination frequency (Shaikh et al., 2007; Zorc et al., 2005).

The presence of significant numbers of bacteria in the urine, however, might also not be associated with symptoms and is termed asymptomatic bacteriuria (ABU). ABU is probably the most common form of UTI with varying prevalence by age, gender, sexual activity and the presence of the genitourinary abnormalities (Table 1). ABU patients may carry more than 105 bacteria/ml of urine for years, but do not develop symptoms (Lindberg et al., 1978).

Asymptomatic bacteriuria is very common among elderly people with frequencies of colonisation ranging from 17 to 50 % in women and 6 to 34 % in men. However, 5% of young school girls will also be asymptomatically colonized once until the age of 15 (Raz, 2003). Women with diabetes are reported to encounter ABU three-fold more often than nondiabetics (Nicolle et al., 2006). In elderly patients with indwelling catheters draining in an open system, the incidence of bacteriuria is almost 100% and the vast majority of them are asymptomatic.

Table 1: Prevalence of asymptomatic bacteriuria in selected populations (Colgan et al., 2006).

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Escherichia coli is the most common organism isolated from patients with ABU, however, other species like Pseudomonas aeruginosa, Enterococcus spp., and group B streptococci are

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reported (Colgan et al., 2006). The microflora in patients with asymptomatic bacteriuria will be influenced by patient variables: healthy persons will likely be colonized by E. coli, whereas a nursing home resident with a catheter will most likely be colonized with a multidrug-resistant polymicrobic flora (e.g., P. aureginosa). Enterococci and Gram- negative bacteria are common in men (Warren et al., 1982) The treatment of asymptomatic bacteriuria is not always beneficial. Depending on the group of patients, if left untreated ABU protects from symptomatic infections (Hansson et al., 1989a), and recurrences of bacteriuria after treatment occur in 50 % to 80 % of patients (Hansson et al., 1989b). However, antibiotic treatment of ABU in pregnant women, patients prior to surgery and those with vesicoureteral reflux has been shown to be beneficial, if not necessary (Nicolle, 2006).

2.2. Escherichia coli as a pathogen 

E. coli is a residential bacterium of the large intestine where it co-exists with the human host and both experience mutual benefits. However, there are several highly adapted clones that have acquired specific virulence attributes which confer an increased ability to colonize new niches and allows them to cause a broad spectrum of disease (Kaper et al., 2004). A subset of E. coli is capable of causing enteric/diarrhoeal diseases and another subset causes extraintestinal diseases. Among the intestinal pathogens, there are six well-described pathotypes: enteropathogenic E. coli (EPEC), enterohaemorrhagic E. coli (EHEC), enterotoxigenic E. coli (ETEC), enteroaggregative E. coli (EAEC), enteroinvasive E. coli (EIEC) and diffusely adherent E. coli (DAEC) (Kaper et al., 2004). The E. coli pathotypes implicated in extraintestinal infections have been called ExPEC (Russo and Johnson, 2000).

UTIs are the most common extraintestinal E. coli infections and are caused by uropathogenic E. coli (UPEC).

Phylogenetic studies have shown that E. coli can be allocated to four main phylogenetic groups, designated ECOR (E. coli group of reference strains) group A, B1, B2 and D (Herzer et al., 1990). Most strains responsible for UTI and other extraintestinal infections belong to ECOR group B2, or to a lesser extent, to group D, and they carry virulence determinants that are absent in ECOR group A and B1 strains (Johnson and Stell, 2000; Picard et al., 1999).

Most of the commensal strains belong to ECOR group A. The various pathotypes of E. coli

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tend to be clonal and are characterized by shared O (lipopolysaccharide, LPS) and H (flagellar) antigens that define serogroups (O antigen only) or serotypes (O and H antigens) (Kaper et al., 2004).

Pathogenic E. coli strains are often characterized by the presence of specific virulence traits that contribute to their pathogenic potential and characteristically are absent among commensal strains (Johnson, 1991; Johnson and Stell, 2000; Kaper et al., 2004). Multiple studies on a number of UPEC strains implicate a variety of virulence and fitness factors that play an important role for urinary tract infection (Fig. 1). Generally, virulence and fitness factors can be grouped as adhesins, toxins and bacteriocins, iron acquisition systems, O-, Kantigens and serum resistance.

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Fig. 1: Pathogenesis of urinary tract infection caused by uropathogenic E. coli. The figure shows the different stages of an ascending urinary tract infection and the involvement of particular virulence factors in that process (Kaper et al., 2004).

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