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org & 2007 International Society of Nephrology

mini review

Role of P-fimbrial-mediated adherence in pyelonephritis and persistence of uropathogenic Escherichia coli (UPEC) in the mammalian kidney
MC Lane1 and HLT Mobley1
1

Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, Michigan, USA

P fimbria, a mannose-resistant adhesin of uropathogenic Escherichia coli (UPEC), has been shown to be associated with acute pyelonephritis. The pap gene cluster encodes the proteins required for P-fimbrial biogenesis, including papG, which encodes the tip adhesin. The three most studied PapG molecular variants, which are shown to bind distinct isoreceptors, are PapGI, -II, and -III. PapGII preferentially binds globoside, or GbO4, a glycolipid isoreceptor of the human kidney. Studies using different animal models of ascending urinary tract infection (UTI) have demonstrated a variable role for P fimbriae, and specifically PapGII-mediated adherence, in renal colonization. The disparities in the results obtained from those studies are likely to be attributed to the differences in animal models and UPEC strains utilized. One explanation that is discussed in detail is the contribution of multiple fimbriae of UPEC that potentially mediate adherence to the mammalian kidney. Overall, P fimbriae appear to play some role in mediating adherence to uroepithelial cells in vivo and establishing an inflammatory response during renal colonization, thus contributing to kidney damage during acute pyelonephritis. To verify that P fimbriae contribute to the pathogenesis of UPEC during ascending UTI (and in particular acute pyelonephritis), future studies should be conducted to satisfy fully all three tenets of the molecular Kochs postulates, including complementation of a mutated allele.
Kidney International (2007) 72, 1925; doi:10.1038/sj.ki.5002230; published online 28 March 2007 KEYWORDS: uropathogenic E. coli; UPEC; P fimbriae; PapG; adherence; pyelonephritis

Correspondence: HLT Mobley, Department of Microbiology and Immunology, University of Michigan Medical School, 5641 Medical Science Building II, 1150 West Medical Center Drive, Ann Arbor, Michigan 48109, USA. E-mail: hmobley@umich.edu Received 2 February 2007; accepted 13 February 2007; published online 28 March 2007
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While the urinary tract of a healthy adult is generally sterile, it is also the most common site of bacterial infection. In general, urinary tract infections (UTIs) develop in an ascending manner beginning with peri-urethral colonization, followed by ascension of the urethra into the bladder causing cystitis, and in some cases if left untreated, ascension of the ureters into the kidneys establishing acute pyelonephritis. Acute pyelonephritis is considered the most serious UTI as it is known to typically cause scarring of the kidney, which may in turn lead to irreversible kidney damage, kidney failure, and/or sepsis. In more than 80% of all uncomplicated acute pyelonephritis cases, the etiologic agent is uropathogenic Escherichia coli (UPEC).1 An important stage in the successful colonization of the urinary tract and pathogenesis of UTI is the ability of UPEC n et al.2 to adhere to host uroepithelia. In 1976, Ede demonstrated that E. coli isolated from the urine of patients with acute symptomatic pyelonephritis adhered in greater numbers to exfoliated uroepithelial cells than E. coli isolated from the urine of patients with asymptomatic bacteriuria. Two years later, the ability of UPEC to attach to human uroepithelial cells was attributed to the presence of mbriae (or pili), which appear as hair-like appendages that protrude from the surface of bacteria.3 These mbriae were determined to be distinct from the common mbriae (otherwise known as type 1 mbriae) in that they mediated adherence to uroepithelial cells in the presence of mannose, a known inhibitor of type 1-mediated adherence.3 The most extensively studied adhesin, and also the rst virulence-associated factor identied for UPEC is P mbria. P mbriae, encoded by the pap (pyelonephritis-associated pili) genes, are signicantly prevalent among strains of UPEC that cause pyelonephritis4 and are characterized by their mannose-resistant adherence to Gal(a14)Galb moieties present in the globoseries of membrane glycolipids on human erythrocytes of the P blood group and on uroepithelial cells5,6 (for a good review on the discovery and characterization of P mbriae, see Johnson7 and Jones et al.8). Structurally speaking, they are composed of B1000 copies of the major subunit protein, PapA, which polymerize to form a rigid stalk that is connected to a exible tip consisting of limited copies of the minor subunit proteins,
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PapE and PapF, and receptor-binding adhesin, PapG, at the distal end.9,10
THE THREE CLASSES OF PapG ADHESINS AND THEIR PREVALENCE AMONG DIFFERENT UPEC ISOLATES

P mbriae are chromosomally encoded by the pap gene cluster, consisting of 11 genes, including papG, which encodes the P-mbrial adhesin. Upon characterization of the PapG adhesin of UPEC isolate J96, Lund et al.11 identied an additional structurally related mbrial gene cluster, prs (pap-related sequence). While Prs mbriae were shown to be serologically identical to P mbriae (of the F13 serotype), they displayed a different receptor-binding specicity.11 The differences in receptor-binding specicity were attributed to the adhesins, PapG and PrsG; in particular, trans-complementation of a P-mbrial adhesin mutant (DpapG) with prsG altered the binding specicity to that of Prs mbriae.11 mberg et al.12 conducted a study Two years later, Stro comparing the binding specicities of PapG and PrsG of strain J96, and PapG from UPEC isolates IA2 and AD110 (of the F72 and F11 P-mbrial serotypes, respectively). Specically, the four G adhesins were examined for binding to puried glycolipids and mammalian erythrocytes and uroepithelial cells. From those studies, they determined that the four G adhesins represent three different isoreceptorbinding variants (PapGI, -II, and -III). The isoreceptors bound by the different PapG variants all contain a common Gal(a14)Gal moiety linked to a ceramide group, which anchors the receptor in the lipid bilayer.13 However, the isoreceptors vary in the number of N-acetylgalactosamine moieties added to the distal Gal(a14)Gal core, or by the addition of sialic acid residues to form more complex receptors.14,15 The type and distribution of the particular isoreceptors among different host tissues and the different binding preferences of the three PapG variants have been shown to contribute to the differences in host tropism of P-mbriated E. coli.12 It was originally described that PapGI adhesins preferentially bind globotriaosylceramide or GbO3 (abundant on human uroepithelial cells), PapGII adhesins preferentially bind globoside or GbO4 (abundant on human uroepithelial cells), and PapGIII adhesins (or PrsG) preferentially bind Forssman antigen or GbO5 (predominant on canine, but not human uroepithelial cells).14 However, additional studies have demonstrated that the PapG variants, in particular PapGIII, bind to other isoreceptors present in the urinary tract of humans.1517 Recently, additional minor PapG variants (of PapGI) as well as a new class of PapG variants (PapGIV) have been reported.18,19 The isoreceptors for which these new PapG variants bind is currently unknown. Therefore, as we discover more isoreceptors and more major or minor PapG variants, we can better understand the host tropism and how it relates to a particular PapG variant. Clinically, the class II papG allele is primarily associated with human pyelonephritis and bacteremia and the class III
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papG allele is associated with human cystitis and with genitourinary infections in dogs and cats.2025 Interestingly, the prevalence of the class II papG allele decreases in UPEC strains isolated from adults with acute pyelonephritis and urinary tract abnormalities and/or obstruction.26 Owing to the rarity of the class I pap allele, not much is known about its clinical association. The class of PapG variant and the chromosomal location of pap alleles typically differ among UPEC strains. The pap gene clusters reside within pathogenicity islands that are acquired by horizontal transfer and inserted within or adjacent to specic tRNA genes. For example, in the pyelonephritis isolates, CFT0732729 and J96,30,31 two pap gene clusters reside in separate pathogenicity islands near the pheU and pheV tRNA genes. Interestingly, both papG genes from CFT073 encode the PapGII adhesin variant, while the two papG genes from J96 encode the PapGI and PapGIII adhesin variants. UPEC cystitis isolate UTI8932,33 and UPEC pyelonephritis isolate 53634,35 have a single pap gene cluster, which is contained in one pathogenicity island that is inserted near the leuX tRNA gene. Both papG genes from UTI89 and 536 encode the PapGIII adhesin variant. UPEC bacteremia isolate, CP9 (J96-like) has been shown to contain two papG alleles that encode the PapGI and PapGIII variants.36 Lastly, UPEC bacteriuria isolate IA2 and pyelonephritis isolates AD110 and DS17 all contain a single pap gene cluster that encodes the PapGII variant.12,3739 Figure 1 illustrates the conservation of amino-acid sequences between the different PapG variants. Each of the PapG adhesin sequences from UPEC strains J96, CP9, IA2, CFT073, DS17, 536, and UTI89 were obtained from Entrez PubMed and aligned using ClustalW software (MegAlign, Lasergene 7). It is hypothesized that the differences in the PapG amino-acid sequences allow for alterations in adhesin binding and host specicity. Recently, both the solution structure of the PapGII adhesin domain and the crystal structure of the PapGII receptor bound to GbO4 (predominant isoreceptor of the human kidney) as well as the unbound form of the adhesin have been determined using multidimensional nuclear magnetic resonance and the multiwavelength anomalous dispersion phasing method.40,41 In Figure 1, residues of PapGII that have been shown to be involved in GbO4 receptor binding are boxed in red.40 Using a series of sophisticated modeling programs, Dodson et al.40 were also able to predict the residues of PapGIII that make contact with GbO5; in Figure 1, for comparison with the PapGII-binding residues, the predicted contact residues of PapGIII are boxed in green. This highlights the structural conservation among PapG variants, while showing the divergence leading to altered receptor specicities.
CONTRIBUTION OF P-FIMBRIAL-MEDIATED ADHERENCE TO PYELONEPHRITIS AND THE PERSISTENCE OF UPEC IN THE MAMMALIAN KIDNEY

Since the discovery of P mbriae, it has been hypothesized that these adhesins contribute to the pathogenesis of UPEC
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Figure 1 | Amino-acid sequence alignment of the three major PapG (or PrsG) adhesin variants from UPEC strains J96, CP9, CFT073, IA2, DS17, 536, and UTI89. The amino-acid sequences, obtained from Entrez PubMed, are presented in single-letter code. The different PapG variants are divided by a solid line. Residues that are homologous to the consensus (which is not shown) are shaded in yellow. Residues that are not homologous to the consensus are shaded in blue. Residues of PapGII that have been shown to be involved in GbO4 receptor binding are boxed in red.40 Residues of PapGIII that have been predicted to be in contact with GbO5 are boxed in green.40

within the mammalian urinary tract. An earlier study, conducted in 1987, demonstrated that the serum of female patients with symptoms of pyelonephritis contained Pmbrial antibodies, suggesting that P mbriae were expressed during infection.42 Similarly, another study conducted shortly thereafter demonstrated that bacteria obtained from midstream or catheterized urine specimens from patients with E. coli cystitis expressed type 1 and P mbriae.43 Thus, both studies provided compelling evidence for the in vivo expression of P mbriae during human UTI. To determine precisely the contribution of P mbriae to the pathogenesis of UPEC, additional studies have been conducted using different animal models of infection. In 1985, OHanley et al.44 determined the distribution and density of the P-mbrial receptor within the urinary tract of BALB/c mice to elucidate the molecular basis for renal colonization. Using the mouse model of ascending infection, they demonstrated that a Gal-Gal pili producing transformant of the nonpathogenic E. coli strain HB101 (obtained by cloning random segments of a UPEC strain J96 cosmid
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library into a moderate copy plasmid) was able to colonize the kidneys of BALB/c mice in the absence of vesicoureteral reux unlike the nonpiliated HB101 parent strain.44 Moreover, subcutaneous and intramuscular vaccination of the mice with puried Gal-Gal pili before infection could block renal colonization upon infection with the Gal-Gal pili producing UPEC strain J96.44 A similar study, conducted by Hagberg et al.45 in 1983, also utilized UPEC strain J96 as a donor to transform fecal-commensal E. coli strain 506 with the pap gene cluster. In particular, they demonstrated that transformants of 506 that contained the pap gene cluster persisted within the kidneys of CBA and BALB/c mice more efciently than did the pap-negative transformants.45 It is important to note that in both studies, wild-type UPEC levels of pyelonephritis were never achieved with the commensal E. coli pap transformants, suggesting that factors other than P mbriae are needed for optimal renal colonization. Furthermore, while both studies demonstrate that addition of P mbriae to a commensal E. coli strain can allow for better colonization, they do not prove that P mbriae are
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required for UPEC pathogenesis or that they contribute to the tness of UPEC during UTI. To determine whether P mbriae are indispensable for UPEC pathogenesis, isogenic P-mbrial mutants of different UPEC strains have been constructed and studied in different animal models of ascending UTI. The rst study to investigate the tness of an isogenic P-mbrial mutant during ascending UTI was conducted by Hagberg et al.,45 along with the P-mbrial transformant studies as described previously. In particular, they demonstrated that a UPEC strain lacking P mbriae was signicantly outcompeted by wild-type UPEC in the kidneys of CBA and BALB/c mice during mixed infection (or co-challenge).45 However, mutants in that study were generated with the use of chemical mutagenesis; since chemical mutagenesis often causes secondary mutations, it would be impossible to know whether the outcompetition of the P-mbrial UPEC mutant was solely due to loss of P mbriae or some other UPEC factor that was mutagenized. Several years later, our laboratory utilized allelic exchange mutagenesis to create precise deletions of papEFG (pheV copy) and papDEFG (pheU copy), thus creating a double pap mutant of UPEC strain CFT073 (UPEC76) that does not produce P mbriae.46 Upon transurethral inoculation of CBA mice (N 100) with four different inoculum concentrations (105, 106, 107, and 109 CFU) of either CFT073 or UPEC76, it was demonstrated that after 1 week of infection, no signicant differences in organism concentration or histological ndings between the wild-type and double-pap mutant were detected in the urine, bladder, or kidney at any challenge concentration. Thus, it was concluded that P mbriae of UPEC are not required for ascending UTI of CBA/J mice. A primate model of ascending infection has also been used to study the contribution of P mbriae to UPEC pathogenesis, as monkeys are also known to have the PapG adhesin receptors.47 In 1994, Roberts et al.39 demonstrated that an isogenic papG mutant of UPEC strain DS17 (called DS17-8), created by allelic exchange mutagenesis, was equally able to cause bladder infection of cynomolgous monkeys as compared to wild-type DS17, but was unable to cause acute pyelonephritis such as wild-type DS17 in this model as determined by histopathological criteria and the concentration of the DS17-8 mutant within the kidneys. Although the PapG adhesin mutant was shown not to cause pyelonephritis, the establishment of P mbriae as a virulence factor, according to molecular Kochs postulates, has still not been fully satised because of the lack of complementation of the mutant in vivo. In all, the inconsistencies observed between each of the P-mbrial mutant animal studies could be explained by the differences in animal models or UPEC strains utilized. Although both mice and monkeys are known to have receptors for the PapG adhesin, a study conducted in 1995 by Lanne et al.48 has shown that the isoreceptor patterns present within the kidneys of primates and mice differ signicantly, thus possibly contributing to differences in host specicity. Also, different PapG variants expressed by the UPEC strains
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studied (PapGI and -III of J96 and PapGII of CFT073 and DS17) may also result in altered host specicity. Another explanation could include differences in the host immune response to P mbriae, thus allowing some animal strains to be less susceptible than others to P-mbriated UPEC infection. Lastly, because it is known that UPEC may have the capacity to express up to 12 different mbriae, it is conceivable that loss of P-mbrial-mediated adherence and colonization may be compensated for by the expression of another mbrial type (discussed further in the next section). More recent studies have uncovered a molecular crosstalk between innate immune Toll-like receptor 4 binds bacterial lipopolysaccharide signaling and P-mbrial-mediated attachment, which is lipopolysaccharide-independent (for a good review see Bergsten49). Upon P-mbrial attachment to its glycosphingolipid receptor, ceramide is released from the lipid part of the receptor; in particular, it has recently been shown that ceramide acts as an agonist of Toll-like receptor 4 and potentially acts as a signaling intermediate between Tolllike receptor 4 and the glycosphingolipid receptor.50 Activation of the Toll-like receptor 4 receptor by P-mbrial attachment subsequently leads to the production of proinammatory cytokines and chemokines (interleukin-6 and CXCL8, respectively) and recruitment of neutrophils.49 Although this proinammatory response is benecial in initiating bacterial clearance, it also causes damage to the surrounding tissue and is associated with renal complications. Since P mbriae are implicated in triggering inammation, it can be deduced that they may also contribute to the pathology and symptoms of acute pyelonephritis.
REDUNDANCY OF FIMBRIAL SYSTEMS IN UPEC

Upon sequencing of the different UPEC genomes, a number of distinct mbrial gene clusters have been identied. For example, the sequencing of UPEC strain CFT073 has revealed 12 putative mbrial gene clusters.29 The most extensively studied mbriae that have been shown to be important in urinary tract colonization are the type 1, P, S, F1C, and Dr/AFA adhesins. Each mbrial type binds distinct isoreceptors found within the mammalian urinary tract: type 1 mbriae bind N-linked oligomannose glycoproteins and uroplakin,51 P mbriae bind Gala(14)bGal moieties present in the globoseries of glycolipids,5,6 S mbriae bind a-sialyl2,3-b-galactoside-containing receptors,52,53 F1C mbriae bind lactosylceramide-containing receptors,54,55 and Dr/Afa adhesins bind the Dr (a ) blood group antigen present on the complement cascade regulator factor, decay-accelerating factor.56 Although these mbriae recognize different receptors, each of the receptors may occupy sites within the same tissue. For instance, type 1, P, S, F1C, and Dr mbriae are all known to bind to different sites within the human kidney (Figure 2). Figure 2 illustrates the sites within the human kidney where distinct mbrial types have been shown experimentally to bind.57 The fact that multiple mbrial types are able to bind to various sites of the human kidney suggests that UPEC are provided with multiple means to
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Figure 2 | Cross-section of the human kidney displaying UPEC fimbrial adhesin-binding sites. Pyelonephritis is considered an ascending infection, where UPEC from the bladder ascend through the ureters into the kidneys. Following ascension, UPEC are known to colonize the collecting ducts, distal and proximal tubules, glomeruli, Bowmans capsules, and the blood vessel walls (see inset). Specific UPEC fimbrial adhesins that have been shown to be involved in attachment to these sites within the kidney are labeled in blue.57

establish renal adherence, thus, contributing to the pathogens overall success during renal colonization. For the most part, E. coli express one mbrial type at a time.58 Thus, it is not surprising that crosstalk occurs between the regulators of the different mbrial systems of UPEC (for a good review see Holden59). Recently, our laboratory and others have demonstrated that loss of one mbrial type leads to expression of another in UPEC. Specically, our laboratory showed that a mutant of UPEC strain CFT073 unable to make type 1 and P mbriae produces F1C mbriae, providing a compensatory mechanism by which UPEC are still able to maintain adherence.60 This compensatory mechanism has also been observed for UPEC strain UTI89, in which a mutant unable to make type 1 pili upregulated expression of S pili (Wright KJ, Seed PC, Hultgren SJ, Abstr. 105th Gen. Meet. Am Soc Microbiol 2005; abstract. B-176: 116). To provide an example, Figure 3 demonstrates that a type 1 mbrial phase-locked derivative of CFT073 that is unable to produce type 1 mbriae (m L-OFF), expresses other mbriae (panels C and D). The type 1 mbrial phase-locked derivative of CFT073 that constitutively expresses type 1 mbriae (m L-ON), which was cultured statically as was the m L-OFF derivative, is shown for comparison (panels A and B). Together, these data demonstrate that there exists a redundancy of mbrial systems in UPEC, which provides UPEC with multiple alternatives to maintain adherence during UTI. Thus, as previously discussed, the lack of importance for P mbriae in the CBA mouse model of infection46 could be explained by the redundancy of mbrial systems in UPEC strain CFT073 (which produces several mbriae, including type 1, P, F1C, and Dr mbriae). In view of the data summarized in Figure 2, it is possible that type 1, F1C, or Dr mbriae may be
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Figure 3 | Transmission electron micrographs of UPEC expressing different fimbriae. (a and b) CFT073 fim L-ON, a mutant that constitutively expresses type 1 fimbriae. (c and d) CFT073 fim L-OFF, a mutant that is unable to express type 1 fimbria produces another type of fimbriae. a and c are at 34 000 magnification, and b and d are at 64 000 magnification.

contributing to the colonization of the murine renal epithelium in the absence of P-mbrial expression.
SUMMARY, CONCLUSIONS, AND FUTURE PERSPECTIVES

P mbriae, the best-studied mbriae and rst virulenceassociated factor described for UPEC, have been shown to be
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associated with acute pyelonephritis. The pap gene cluster encodes the proteins required for P-mbrial synthesis, including papG, the gene encoding the tip mbrial adhesin. Three major and well-studied classes of papG alleles exist, which encode the molecular variants PapGI, -II, and -III. Each PapG variant is known to have a distinct isoreceptor specicity, which in turn results in altered host tissue tropism. PapGII, which is clinically associated with acute pyelonephritis in humans, has been shown to bind preferentially globoside, or GbO4, the predominant glycolipid isoreceptor of the human kidney. Various research using different animal models of ascending UTI have found a variable role for P mbriae, and in particular PapGIImediated adherence, in the colonization of the mammalian kidney. The disparities in the results obtained from those studies are likely to be attributed to the differences in animal models and UPEC strains utilized. One likely explanation that was discussed in detail was the fact that UPEC produce several different mbrial types that are also known to bind to different regions of the human kidney, and therefore, when P mbriae are unable to be expressed, other mbriae could compensate for their loss. Overall, it appears that there is a subtle role for P mbriae in mediating adherence to uroepithelial cells in vivo and establishing a robust inammatory response during renal colonization, which in turn contributes to kidney damage during acute pyelonephritis. To verify that P mbriae contribute to the pathogenesis of UPEC during ascending UTI (and in particular acute pyelonephritis), future studies should be conducted to satisfy fully all three tenets of the molecular Kochs postulates, including complementation of a dened mutation. Furthermore, it may be advantageous to investigate the spatial and temporal expression of P mbriae (and other mbrial types) during in vivo ascending infection to determine more precisely the role and expression prole of P mbriae (and other mbriae) during kidney colonization.
ACKNOWLEDGMENTS

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We sincerely apologize to the authors of publications that could not be included in this review due to space limitations. This work was supported by Public Health Service grant AI43363 and AI059722 from the National Institutes of Health.
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