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

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Interestingly, pre-incubation of catheters with strain 83972 has been reported to prevent colonisation by bacterial or fungal uropathogens (Darouiche et al., 2001; Trautner et al., 2003). In all these cases, a controlled asymptomatic bacteriuria with strain 83972 did not jeopardize the health of the patients and reduced the necessity of antibiotic treatment. Thus further scientific efforts are required to establish colonisation with strain 83972 as a potential prophylactic approach against symptomatic UTI in a routine manner. Such an approach certainly improves the quality of life of people suffering from chronic UTI infections and reduces occurrence of antibiotic resistance.

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2.4. Mechanisms of pathogen recognition   The variation in urinary tract virulence reflects the ability of bacteria to trigger mucosal and systemic host responses. Through different molecular interactions bacteria may activate cellular responses, cause cell detachment, and invade or kill cells by apoptosis (Svanborg et al., 2001). Attachment to the mucosa is an essential step in pathogen recognition that activates the host defence signalling pathways (Bergsten et al., 2004). UPEC use type 1-, F1C- and Pfimbriae for epithelial cell adherence at different stages of the infection (Johnson, 1991;

Mobley et al., 1994; Wullt et al., 2002).

Type 1- and P-fimbriated E. coli share the ability to activate epithelial cells, but they differ in receptor specificity. In case of P fimbriae, the receptors are glycosphingolipids with Galα(1Galβ receptor motifs, and the PapG tip adhesin binds to these oligosaccharide epitopes (Fischer et al., 2006). Type 1 fimbriae bind to mannose-containing oligosaccharides on bladder epithelial cells (Svensson et al., 1994). Host response to these two fimbriae is controlled by the Toll-like receptor 4 (TLR4), but different adaptor proteins are involved in the down-stream signalling (Fischer et al., 2006).

LPS as a principal component of the Gram-negative cell suface (Yang et al., 1999). Its recognition is mediated by CD14 that subsequently interacts with TLR4 (Beutler, 2000), followed by down-stream signalling. However, Samuelsson et al. (2004) demonstrated that CD14 is not expressed by the urinary tract epithelium. Therefore, the expression of fimbriae but not the presence of LPS-“coated” bacteria per se decides about the quantity of the host response (Svanborg et al., 2006).

Down-stream signalling causes transcriptional activation and production of inflammatory mediators in the epithelial cell. As a result, chemotactic substances are secreted that include the chemokines IL 6 and IL 8 (Agace et al., 1993a). A chemotactic gradient is created and, in response to the gradient, neutrophils leave the bloodstream, migrate through the tissues and cross the epithelial barrier into the lumen (Agace et al., 1993b; Godaly et al., 1997; Hang et al., 1999). Neutrophils (PMNs) are phagocytes, capable of ingesting microorganisms or particles. They can internalise and kill many microbes by the formation of a phagosome into which reactive oxygen species and hydrolytic enzymes are secreted. Neutrophils have been shown to increase 43-fold expression of the inducible nitric oxide synthase (iNOS) during UTI when compared to non-infected controls (Wheeler et al., 1997). As a consequence, the

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nitric oxide concentration in the urine during UTI is increased 30 to 50 times (Lundberg et al., 1996).

2.5. Nitric oxide - a host defence mechanism   Nitric oxide (NO) at concentrations of approximately 10-7 M controls blood pressure in mammals and is a messenger in the central and peripheral nervous system (Fang, 2004). In addition to its natural physiological function, NO is a defence molecule against microbial infections (Bang et al., 2006; Bogdan, 2001; Coban and Durupinar, 2003; Fang and VazquezTorres, 2002). Nitric oxide is potentially reactive because of the physical instability of oxygen- or nitrogen-based unpaired electrons in their orbits, which leads to a number of deleterious pathological consequences in vivo (Akaike, 2001). NO, being a lipophilic radical, diffuses across cell membranes and through the cytoplasm. Sustained NO generation by macrophages inhibits at higher concentrations key enzymes including terminal oxidases and other haem-containing enzymes that bind dioxygen, and Fe-S centres in enzymes such as aconitase. Toxic effects may also arise from reactions involving nitrosation or the peroxynitrate, formed from the reaction of NO with a superoxide anion (Hughes, 1999).

These products may store NO or exert toxic effects while their formation may initiate redox or conformational changes (Poole, 2005).

One particularly important effect of NO in the biological systems is its ability to cause genomic alterations (Sakai et al., 2006; Weiss, 2006; Wink et al., 1991). When DNA is exposed in vitro to HNO2 or to NO, the exocyclic amines of the nucleobases form unstable Nnitroso (-N-N = O) derivatives that lead to deamination. Thus, adenine is deaminated to hypoxanthine, guanine is deaminated to xanthine, and cytosine is deaminated to uracil (Shapiro and Pohl, 1968). The deaminated products pair with different bases than their aminated counterparts. Therefore, they almost always produce mutations during subsequent replication. Nitrosation of cellular secondary amines and amides produces alkylating agents that cause mutagenic lesions at many sites in DNA (Victorin, 1994). Other DNA lesions include interstrand and intrastrand cross-links, protein-DNA cross-links, the formation of oxanine from guanine (Suzuki et al., 2000), and DNA replication block, which leads to base substitutions and single-base frameshifts involving translesion DNA synthesis (Sakai et al., 2006).





27   Introduction 

NO and its congeners exert toxic effects, and microbes have evolved a number of mechanisms for coping with these reactive nitrogen species and their derivatives. Enteric bacteria, such as E. coli and Salmonella enterica serovar Typhimurium, use two major mechanisms to detoxify NO, the flavohemoglobin Hmp and the flavorubredoxin NorV (Poole et al., 1996; Poole, 2005). The flavohemoglobin detoxifies NO by an O2-dependent denitrosylase mechanism, producing NO3- under aerobic or microaerobic conditions or by the slower O2-independent reduction of NO to N2O (Poole, 2005). The flavoruboredoxin NorV along with its cognate reductase, NorW, however, catalyzes the reductive detoxification of NO only under microaerobic or anaerobic conditions (Gardner et al., 2002). The periplasmic cytochrome c nitrate reductase NrfA, which reduces NO2- toNH3, may also be able to directly reduce NO (Poock et al., 2002).

NO in the living cell interacts with biomolecules within its immediate environment and forms other reactive nitrogen species (RNS), such as S-nitrosoglutathione (GSNO) and nitrosothiols through interactions with glutathione (GSH) and thiols, respectively (Kidd et al., 2007). The GSH-dependent formaldehyde dehydrogenase AdhC is conserved from man to bacteria and has GSNO reductase activity (Liu et al., 2001), which can limit levels of S-nitrosoglutathione during nitrosative stress. Recently, it has been shown that AdhC is required for the defence against nitrosative stress in Haemophilus influenzae (Kidd et al., 2007), however, its function in Salmonella enterica serovar Typhimurium remains unclear (Bang et al., 2006).

2.6. Genome plasticity and bacterial evolution 

Genome evolution is a continuous process that comprises long-term ‘macroevolution’ which over millions of years leads to the development of new species, and a short-term ‘microevolution’ that alters already existing species/pathotypes enabling them to colonize new environmental niches (Ziebuhr et al., 1999). However, continuously changing environmental conditions force bacteria to start adaptive process. Along regulatory responses that act at the expression level, microorganisms must have evolved strategies allowing the generation of genetic diversity (Arber, 1993). Point mutations, recombination between homologous DNA sites, and the action of transposable genetic elements are major mechanisms by which genome flexibility is achieved (Fig. 3). The capture and spread of genes by horizontal gene transfer involving plasmids, phages and other mobile elements also

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contribute to this process. Finally, the clustering of genes on large genomic island and their mobilization enables bacteria to gain or lose huge amounts of DNA involved in adaptation to distinct ecological niches (Ziebuhr et al., 1999).

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Fig. 3.: Bacterial genome plasticity. There are three main forces that shape bacterial genomes: gene acquisition, gene loss and gene variation. All three can occur in a single bacterium. Some of the changes that result from the interplay of these forces are shown.

E. coli migrating from the large intestine, its natural reservoir, to the urinary tract have to face challenging new conditions, incl. different growth rates, nutrient limitation, host response, and urodynamics in the bladder. Successful colonisation of this niche requires bacterial adaptation to these conditions. Therefore genome alterations in combination with selective pressure will contribute to that process.

Point mutations are considered as driving forces in a slow evolutionary process. During replication, point mutations can be generated by slipped-strand mispairing, resulting in expression or non-expression of particular genes (Leathart and Gally, 1998). Regulatory genes which control coordinated gene expression under changing environmental conditions have also been found to be subject to point mutations and small deletions (Hengge-Aronis, 1999). Some mutations, so called ‘pathoadaptive’ mutations, enable single bacterial clones to become more pathogenic without the acquisition of additional genes. This mechanism is

29   Introduction 

based on random mutagenesis which offers the bacterium a strong advantage under a selective pressure (Sokurenko et al., 1999). In addition to the modification of structural and regulatory genes, point mutations also contribute to the development of bacterial resistance to antibiotics (Musser, 1995).

The generation of large deletions of the bacterial chromosome represents another major principle of genome plasticity. Excisions are frequently observed in Streptomyces spp., where large deletions comprising up to 800 kb of DNA occur (Birch et al., 1991). Recently it has been shown for the ABU strain 83972 that an internal deletion of 4.2 kb DNA stretch resulted in inactivation of type 1 fimbriae (Klemm et al., 2006).

Bacterial insertion sequence (IS) elements are small mobile DNA units encoding only for features necessary for their own mobilization and mediate mutations and DNA rearrangements in bacteria (Mahillon and Chandler, 1998). IS elements can be regarded as repetitive DNA sequences, randomly distributed on the bacterial chromosome that have the capacity to cause inactivation of genes by random and in some cases also by site-specific transposition. In addition to simple transposition, IS elements also give rise to complex DNA rearrangements including deletions, inversions, gene amplifications and the fusion of two DNA molecules by co-integrate formation (Arber, 1993).

Another way of genome rearrangements is acquisition or loss of particular regions on the bacterial chromosome, termed ‘pathogenicity islands’ (PAI) (Hacker et al., 1997; Hacker and Kaper, 2000). Similarly, there are DNA regions that do not contain virulence-associated genes, but nevertheless contribute to the fitness of the bacterium. These so-called genomic islands (GEIs) encode for additional traits that may be beneficial for the bacteria under certain growth conditions (Hacker and Carniel, 2001). Genomic islands represent (formerly) mobile DNA elements and are considered to have been acquired by horizontal gene transfer, thereby contributing to the evolutionary potential of bacteria (Dobrindt et al., 2003; Hacker et al., 2003).

2.7. Bacterial population dynamics   Biologists have long been interested in the observation of the dynamics of evolutionary changes. Charles Darwin remarked: “in looking for the gradations by which an organ in any

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species has been perfected, we ought to look exclusively to its lineal ancestors;  but this is scarcely ever possible, and we are forced in each case to look to species of the same group, that is to the collateral descendants from the same original parent-form” (Darwin, 1872).

However, Darwin could only use a comparative approach by necessity, evolution nowadays can be assessed in action. Beyond simply observing evolution in nature, some biologists sought to carry out experiments that ran for many generations, with controls and replication, to test hypotheses  about the evolutionary process. In this context, microbial evolution experiments have received increasing attention.

Richard Lenski captures microbial evolution in a conceptually simple approach: Populations are established from single clones, then propagated in a controlled and reproducible environment for many generations. A sample of the ancestral population is stored indefinitely (for example, frozen at –80 °C), as are samples from various time points in the experiment.

After a population has been propagated for some time, the ancestral and derived genotypes can be compared with respect to any genetic or phenotypic properties of interest, which provides information on the dynamics of the evolutionary process and the extent of evolutionary change. Importantly, adaptation can be quantified by measuring changes in fitness in the experimental environment, in which fitness reflects the propensity to leave descendants (Lenski et al., 1991).

The very extensive work of Lenski and colleagues resulted in many interesting conclusions.



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