**6. Structure of adhesins**

Adhesins, which appear as hair-like fibers called fimbriae (or pili), facilitate the colonization with *E. coli* in the urinary tract by attaching to host epithelial cells. This attachment promotes the persistence of the organism in the bladder, and serves as a reservoir for ascending infection in the urinary tract [27].

Various adhesins have been identified and are classified mainly according to receptor specificity, with some being mannose resistant and others sensitive. P fimbriae (or pili), the best-described group of mannose-resistant adhesins of UPEC, are so named because they specifically bind to the Gal(α1–4) Gal disaccharide galabiose, which is an antigen within the human P blood group system [26]. Different components of the P fimbriae have been described, including four different units that are at the tip of the fibrillum, including PapG, PapE, PapF, and PapK [28–30]. These fimbrial proteins and other accessory proteins are encoded by a chromosomal multicistronic gene cluster termed *pap* (pilus associated with pyelonephritis), which can be carried on large chromosomal insertions called pathogenicity associated islands (PAIs) [31].

Actual attachment of the organism to host epithelial cells is effected through PapG by recognition of glycolipid receptors expressed on host kidney cells and red blood cells [32]. Three variants of PapG, encoded by distinct alleles of the corresponding gene, *pap*, have been identified, namely PapGI, PapGII, and PapGIII [32–34]. Most studies indicate that allele II is the main PapG variant in *E. coli* bacteremia (regardless of primary source), acute pyelonephritis, and acute prostatitis, whilst allele III predominates in acute cystitis [33, 9]. Other studies found statistically significant associations between allele III and several compromising host conditions, such as urinary anatomical abnormalities, diabetes [33, 35].

Type 1 fimbriae are the commonest adhesive organelles of *E. coli*. They mediate adhesion of the organism to secreted and cell-bound mannosylated glycoproteins and exhibit mannose sensitive hemagglutination of guinea pig erythrocytes [36]. The ubiquitous distribution of these fimbriae in *E. coli* makes it difficult to show an association with UTI outside an experimental setting. However, type 1 fimbriae exhibit several different phenotypes due to allelic variation of the gene for the lectin subunit, fimH, and these phenotypes have been shown to be distributed differentially among fecal and UTI isolates [37–39]. Type 1 fimbriae are encoded by a chromosomal fim gene cluster that contains genes for a structural subunit, an adhesin, several accessory proteins, and regulatory proteins (fimACDFGH) [30, 39].

**5. Uropathogenic** *E. coli* **(UPEC) and virulence factors (VFs)**

48 *Escherichia coli* Escherichia coli - Recent Advances on Physiology, Pathogenesis and Biotechnological Applications - Recent Advances on Physiology, Pathogenesis and Biotechnological Applications

shown that none uniquely defines these pathogens.

**6. Structure of adhesins**

in the urinary tract [27].

associated islands (PAIs) [31].

Virulence refers to the ability of an organism to cause disease, and is a function of the presence of distinct accessory traits, referred to as virulence factors (VFs). VFs are specific properties that enable organisms to overcome host defenses and cause disease [26]. However, although several VFs have been identified in UPEC, experimental and epidemiological data have

UPEC VFs are grouped by functional categories as adhesins, toxins, iron acquisition systems, and protectins. VFs are encoded by genes located on chromosomes or plasmids, with some being exclusively chromosomal (e.g., *pap* and *hly*), others exclusively or principally plasmid-associated, e.g., *iss* and *traT*, and some either chromosomal or plasmid-associated (*afa*). Consequently, VFs may be vertically or horizontally transmitted, further contributing to the complexity of understanding the role played by specific VF genes in UTI pathogenesis.

Adhesins, which appear as hair-like fibers called fimbriae (or pili), facilitate the colonization with *E. coli* in the urinary tract by attaching to host epithelial cells. This attachment promotes the persistence of the organism in the bladder, and serves as a reservoir for ascending infection

Various adhesins have been identified and are classified mainly according to receptor specificity, with some being mannose resistant and others sensitive. P fimbriae (or pili), the best-described group of mannose-resistant adhesins of UPEC, are so named because they specifically bind to the Gal(α1–4) Gal disaccharide galabiose, which is an antigen within the human P blood group system [26]. Different components of the P fimbriae have been described, including four different units that are at the tip of the fibrillum, including PapG, PapE, PapF, and PapK [28–30]. These fimbrial proteins and other accessory proteins are encoded by a chromosomal multicistronic gene cluster termed *pap* (pilus associated with pyelonephritis), which can be carried on large chromosomal insertions called pathogenicity

Actual attachment of the organism to host epithelial cells is effected through PapG by recognition of glycolipid receptors expressed on host kidney cells and red blood cells [32]. Three variants of PapG, encoded by distinct alleles of the corresponding gene, *pap*, have been identified, namely PapGI, PapGII, and PapGIII [32–34]. Most studies indicate that allele II is the main PapG variant in *E. coli* bacteremia (regardless of primary source), acute pyelonephritis, and acute prostatitis, whilst allele III predominates in acute cystitis [33, 9]. Other studies found statistically significant associations between allele III and several compromising host condi-

Type 1 fimbriae are the commonest adhesive organelles of *E. coli*. They mediate adhesion of the organism to secreted and cell-bound mannosylated glycoproteins and exhibit mannose

tions, such as urinary anatomical abnormalities, diabetes [33, 35].

Phase variation controls the expression of type 1 fimbriae by site specific recombination. A 314-bp phase-variable invertible element, that contains the promoter, controls the transcription of the fimbrial genes fimACDFGH. The promoter drives the expression of type 1 fimbriae when the switch is in the ON orientation but not when it is in the OFF orientation [40]. It has been shown that the expression of type 1 fimbriae coordinately affects the expression of P fimbriae in an inverse manner, providing evidence of a direct communication between genes related to pathogenesis [41, 42].

Although most studies have confirmed that type 1 fimbriae are particularly important in bladder colonization [43, 44], the proportions of UPEC strains from urine and feces expressing type 1 fimbriae appear to be similar [26], ranging from a high of 71% among isolates from cystitis patients to a low of 58% among those from patients with ASB, with fecal strains in the mid-range at 60% [26]. However, in contrast, the level of expression of type 1 fimbriae among UPEC blood isolates (81%) is significantly different from that of fecal strains [45, 46].

Another adhesin family is the Afa/Dr family, which consists of adhesins that include the uropathogen-associated fimbrial adhesin Dr, along with other nonfimbrial adhesins, including Afa-1, Afa-2, Afa-3, Afa 4, NFu1, and Dr-11. These adhesins have a different structure from other *E. coli* fimbrial adhesins in that they appear as fine mesh, a coil-like structure or as a filamentous capsule coating on the cell surface [45, 47, 48]. Epidemiological studies show that *E. coli* strains that express adhesins of the Afa/Dr family are involved in 25–50% of cases of cystitis in children, and 30% of cases of pyelonephritis in pregnant women [49]. Moreover, *E. coli* strains expressing Dr adhesins have been associated with a two-fold increase in the risk of a second UTI. It has also been shown that UPEC encoding the Dr adhesin could survive for more than 1 year within renal tissue [49, 50]. These findings suggest a possible role for Dr/Afa adhesins in recurrent or chronic UTI.

Finally, the closely-related S fimbriae and F1C (fimbriae of serotype 1C), so named because of their binding specificity for terminal sialyl-galactoside residues, mediate X-type mannose resistant hemagglutination of human erythrocytes [51–53]. They agglutinate human and bovine red cells [54, 55]. S fimbriae have a similar, but less well defined, structure to both type 1 and P fimbriae. Just like type 1 and P fimbriae, expression of S fimbriae exhibits phase variation [51]. Binding sites for S fimbriae are located on epithelial cells of the proximal and distal tubules, collecting ducts and glomerulus [55]. In humans, S-fimbriated *E. coli* strains are more closely associated with meningitis and bacteremia than with UTI [56]. They could therefore be important in the movement of the organism from the urinary tract to the blood stream. Few studies have been carried out on the role played by these two types of fimbriae in UTI pathogenesis. FIC fimbriae are expressed by about 14% of UPEC and 7% of *E. coli* fecal isolates [53].
