Gene Structure Of Uropathogens

Studies on the genome structure of uropathogens were performed especially with uropathogenic E. coli3. 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 toE. coli K-12. It is suggested that uropathogenic E. coli may also carry additional 300 to 400 kb ofDNA. 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 ofgreat 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 3 4. 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. coli6. 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 uropathogenicE. coli , the a -hemolysin toxin was described many years ago. Recently, an accumulating amount of data concerning the maturation of the a -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 produced by uropathogenic E. coli, its role in the pathogenesis, however, remains to be elucidated.

Another import feature ofpathogenic bacteria are adherence factors. The fimbriae from uropathogenic E. coli are well described3. It was shown that P-fimbriae, which are able to bind to Gal al-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. S -fimbriae 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 P 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 Proteuspenneri 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.

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