P Adhesins among Wild-Type Escherichia coli - Infection and Immunity

P Adhesins among Wild-Type Escherichia coli - Infection and Immunity

INFECTION AND IMMUNITY, Nov. 1993, p. 4902-4905 0019-9567/93/114902-04$02.00/0 Copyright © 1993, American Society for Microbiology Vol. 61, No. 11 P...

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INFECTION AND IMMUNITY, Nov. 1993, p. 4902-4905 0019-9567/93/114902-04$02.00/0 Copyright © 1993, American Society for Microbiology

Vol. 61, No. 11

P1-Antigen-Containing Avian Egg Whites as Inhibitors of P Adhesins among Wild-Type Escherichia coli Strains from Patients with Urosepsis JAMES R. JOHNSON* AND ALLAN E. ROSS Department ofMedicine, University of Minnesota, Minneapolis, Minnesota 55455 Received 7 June 1993/Returned for modification 30 July 1993/Accepted 26 August 1993

globoside. Globoside's inefficacy may have resulted from a proadherence effect of globoside's lipid tail. Adhesin phenotypes determined with dove and pigeon egg whites as agglutination inhibitors corresponded closely with phenotypes defined by comparative hemagglutination of human P1 and p erythrocytes. These data suggest that avian Pl-antigen-containing substances may provide a useful alternative method for P adhesin inhibition among uropathogenic E. coli strains. P adhesins of uropathogenic Escherichia coli promote urinary tract colonization through their specific attachment to Gal(al1- 4)Gal moieties on host cell surfaces (14, 21, 23, 27, 28). Soluble compounds containing this critical Gal (al->4)Gal moiety inhibit the interaction of P adhesins with surface receptors, presumably by occupying digalactosidebinding sites on P-adhesin molecules (21, 23, 24, 27, 28). Inhibitors of digalactoside-specific adherence are useful in the laboratory characterization of mannose-resistant (MR) adhesins among uropathogenic E. coli strains (19, 26, 34), both for the identification of P adhesins (which mediate digalactoside-sensitive, MR hemagglutination [MRHA] of human erythrocytes) and for the detection of non-P MR (NPMR) adhesins (which mediate digalactoside-independent MRHA of human erythrocytes) (14). Inhibitors of P adhesins are also potentially useful for preventing urinary tract infection (23, 42, 43). Unfortunately, currently available P-adhesin inhibitors are prohibitively expensive (19) or contain a lipid component capable of associating with cell membranes, thereby increasing the P-fimbrial-receptor density and potentially promoting rather than blocking attachment (11, 19). Egg whites of pigeons, doves, and members of the parrot family exhibit high levels of the digalactoside-containing P1 antigen (3, 8, 9, 13, 19, 38) and are potent inhibitors of P adhesins from E. coli J96 (19). However, evidence that the P adhesins of strain J96 are not representative of the P adhesins of most uropathogenic strains is accumulating (6, 31, 41). We therefore undertook the present study to determine whether susceptibility to inhibition by P1 antigen-containing avian egg whites is generally characteristic of wild-type P-fimbriated E. coli and to compare the inhibitory potency of these avian substances with that of globoside, a digalactoside-containing glycolipid, among such strains. Strains. The study population comprised 58 E. coli strains isolated from the blood of patients with urosepsis (18). Information regarding compromising host conditions was obtained from medical records, as previously described (18). Recombinant strains expressing cloned P adhesins (JJ48) (19), F1845 fimbriae (HB101/pSSS1) (2), the Dr hemagglutinin (BN406) (33), S fimbriae (536-21) (10), pap-2-encoded

*

fimbriae (P678-54/pJFK102) (25), both P and F1845 fimbriae (JJ105) (19), or no MR adhesin (HB101) were used as controls (19). Inhibitors. Whole pigeon, dove, and chicken egg whites (PEW, DEW, and CEW) and 2.5 mM globoside in phosphate-buffered saline (PBS) were prepared as previously described (19). The synthetic P1 antigen analog Gal(al-.4) Gal(f31- 34)GlcNAc-O-ethyl (Pl-O-Et; Sigma Chemical Corp., St. Louis, Mo.) was prepared as a 6.0 mM solution in PBS. Inhibitors were used without further dilution. Agglutination reactions. Agglutination reactions were done using suspensions of plate-grown bacteria and human P1 erythrocytes, human p erythrocytes, sheep erythrocytes, and digalactoside-coated latex beads (P beads; Chembiomed, Edmonton, Alberta, Canada) (19), both at room temperature (using room-temperature reagents) and on ice (using iced reagents). As alternative targets for P adhesins, p erythrocytes and P beads were incubated in globoside for 30 min at 37°C, washed in PBS, and resuspended in PBS plus 10% a-D-mannose. The minimal agglutinating concentration (MAC; lowest bacterial concentration giving macroscopic agglutination) for erythrocytes and P beads was determined as previously described (19). P adherence was defined as agglutination of both P beads and P1 erythrocytes but not p erythrocytes; NPMR adherence was defined as agglutination of both P1 and p erythrocytes but not P beads; and P-plus-NPMR adherence was defined as agglutination of P beads and both P1 and p erythrocytes. Failure to agglutinate P beads, P1 erythrocytes, and p erythrocytes was interpreted as evidence of an absence of MR adhesins. Agglutination of globoside-coated P beads or of globoside-coated (but not uncoated) p erythrocytes was used as a surrogate for agglutination of unmodified P beads. To ensure the NPMR specificity of p erythrocyte agglutination, MRHA of p erythrocytes was required to persist in the presence of 6.0 mM P1-O-Et. Strains were considered to express a pap-2-encoded adhesin if they

vigorously agglutinated sheep erythrocytes (1, 25). Agglutination inhibition. All strains that agglutinated P1 erythrocytes on ice underwent qualitative MRHA inhibition tests using CEW, DEW, PEW, and globoside at a bacterial concentration four times the MAC (19). Additionally, for strains that at room temperature exhibited only P adherence,

Corresponding author. 4902

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Among 58 Escherichia coli urosepsis isolates, Pl-antigen-containing dove and pigeon egg whites were significantly more effective inhibitors of P-adhesin-specific agglutination than were chicken egg whites or

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VOL. 61, 1993

TABLE 1. MR adhesin phenotypes of 58 urosepsis strains

No. (%) of strains when assayed:

MR adhesin phenotype category

At room temp

On ice

P only NPMR only P + NPMR Undefined Negative

34 (59) 4 (7) 1(2) 4 (7) 15 (26)

40 (69) 5 (9) 1(2) 1 (2) 11 (19)

TABLE 2. Inhibition of MRHA among 47 urosepsis strains exhibiting MRHA of P1 erythrocytes on ice MR adhesin phenotype

category (n)

P only (40) NPMR only (5) P + NPMR (1)

Undefined (1)

No. of strains with MRHA inhibited by: 2.5 mM globoside DEW PEW

40 1 1 1

a CEW did not inhibit MRHA at all.

40 1 1 1

4 0 0 0

failed to inhibit MRHA altogether (Table 2) (P < 0.001 for all comparisons, DEW or PEW versus globoside or CEW). In quantitative agglutination inhibition assays done with the 34 strains that exhibited P adhesins at room temperature (Table 1), the mean MAC elevation produced by CEW in comparison with the MAC in PBS was slight (1.7-fold for P beads and 1.3-fold for P1 erythrocytes). Similarly, globoside elevated the MAC only 4.0-fold for P beads (P = 0.0007) and 2.6-fold for P1 erythrocytes (P = 0.01). In contrast, DEW and PEW elevated the MAC 29- and 30-fold, respectively, for P beads, and 37- and 75-fold, respectively, for P1 erythrocytes (P = 0.0001 for all comparisons). Compared with globoside, DEW and PEW gave 11-fold-higher MACs for P beads and 23- to 41-fold-higher MACs for P1 erythrocytes (P = 0.0001 for all comparisons). Resistance of P adhesins to inhibition by globoside was evident not only at four times the MAC but even at limiting bacterial dilutions. In contrast, DEW and PEW commonly inhibited agglutination even at the maximal bacterial concentration (data not shown). Mechanism of globoside resistance. Preincubation of several globoside-resistant strains in 2.5 mM globoside for 1 h at 37°C (27, 28) or at 4°C (35) failed to augment agglutination inhibition. Three of five globoside-resistant strains and three of six globoside-sensitive strains agglutinated sheep erythrocytes, evidence that pap-2-encoded adhesins were neither sufficient nor necessary for globoside resistance. A receptor preference for terminal Gal-Gal moieties among globosideresistant strains was excluded as an explanation for poor antagonism of P adhesins by the internal Gal-Gal moiety of globoside, since selected globoside-resistant strains agglutinated P1 erythrocytes and globoside-coated p erythrocytes with similar intensities at a given bacterial concentration. Paradoxically, MRHA of globoside-coated p erythrocytes by these globoside-resistant strains was not inhibited by globoside to any greater extent than was agglutination of P1 erythrocytes, despite the presence of globoside as the presumed sole receptor for P adhesins on the globoside-coated p erythrocytes. Further experiments suggested that globoside's lipid tail was capable of attaching to the surface of erythrocytes, P beads, and bacteria, thus rendering these substrates more agglutinable by P-fimbriated strains. First, fourpap-positive strains, each P adhesin positive when tested on ice, also agglutinated P1 erythrocytes and/or P beads at room temperature, but only in the presence of globoside. Second, P beads coated with globoside were 4- to 16-fold more agglutinable by P-fimbriated strains than were uncoated P beads. Third, globoside, whether preadsorbed to p erythrocytes or added at the time of agglutination testing, made p erythrocytes agglutinable by P-fimbriated strains. Fourth, P-fimbriated strains autoagglutinated in the presence (but not the absence) of globoside, whether globoside was used to coat the bacteria (as described for P beads and p erythrocytes) or was added during agglutination testing. Fifth, globoside-coated (but not uncoated) P-fimbriated strains agglutinated p erythrocytes. Finally, P-fimbriated strains agglutinated globosidecoated (but not uncoated) cells of strain HB101. Thus, we found that DEW and PEW were highly effective P-adhesin inhibitors among wild-type E. coli urosepsis isolates, blocking agglutination with all strains that expressed P adhesins alone and with the one strain that expressed both P and NPMR adhesins. These findings suggest that such avian substances are active against not only the previously studied P adhesin from strain J96 (19) but also the P adhesins of uropathogenic strains in general. This is important because although the J96 P adhesin has been studied in greater detail

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the relative potency of the various inhibitors was determined by comparing the MAC for P beads or P1 erythrocytes in the presence of the inhibitor with the MAC in the presence of PBS alone. pap DNA genotype and statistical methods. Strains were characterized as to the presence or absence of papEFGhomologous sequences (17) by Southern hybridization of total cellular DNA with a 32P-labeled DNA probe derived from the papEFG (adhesin complex) region of pRHU845 (12). Comparisons of proportions were tested by using the chi-square statistic. Comparisons involving MACs were tested by a two-tailed paired t test. MR adhesin phenotypes. Most of the 58 urosepsis strains exhibited only P adhesins, whereas a few exhibited only NPMR adhesins and a single strain expressed both P and NPMR adhesins (Table 1); approximately one quarter were adhesin negative (Table 1). All agglutination reactions positive at room temperature were also positive on ice; additional positive reactions evident only on ice allowed seven strains with a negative or undefined phenotype to be assigned to a specific phenotype category (Table 1). pap status and host characteristics versus MR phenotype. All strains that on ice exhibited P adhesins were pap positive, as were three of the P-adhesin-negative strains (one NPMR-only strain, one adhesin-negative strain, and one strain of undefined phenotype). All six strains that expressed NPMR adherence on ice were from patients with at least one compromising condition (18), and four were from multiply compromised hosts. In contrast, only 41 (78%) of the strains without NPMR adhesins were from compromised hosts, and only 18 (33%) were from multiply compromised hosts. Two (33%) of the strains with NPMR adhesins, compared with only three (6%) of the other strains, were from patients with upper urinary tract abnormalities (P = 0.03). Adhesin inhibition. In qualitative agglutination inhibition assays, DEW and PEW gave nearly identical results and were significantly more effective than CEW or globoside (Table 2). Both PEW and DEW blocked MRHA of P1 erythrocytes for all 41 P-fimbriated strains and for 1 of the 5 NPMR-only strains (Table 2). In contrast, globoside inhibited MRHA for only four P-fimbriated strains, and CEW

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assay temperature on MRHA phenotype should be considered in interpreting the results of such studies. That only 10% of urosepsis blood isolates expressed NPMR adhesins, either alone or together with P adhesins, is consistent with previous reports involving urinary E. coli (7, 23, 30, 37, 40, 44). This finding, in contrast to the high prevalence of P adhesins, suggests that NPMR adhesins contribute comparatively little to the pathogenesis of urosepsis. Nonetheless, associations we found between NPMR adhesins and host compromise suggest that NPMR adhesins may play a role in invasive urinary tract infections specifically among medically or urologically compromised hosts. Jane L. Swanson provided p erythrocytes, and Jodi A. Aasmundrud and Beth Wetak helped prepare the manuscript. REFERENCES 1. Arthur, M., C. E. Johnson, R. H. Rubin, R. D. Arbeit, C. Campanelli, C. Kim, S. Steinback, M. Agarwal, R. Wilkinson, and R. Goldstein. 1989. Molecular epidemiology of adhesin and hemolysin virulence factors among uropathogenic Escherichia coli. Infect. Immun. 57:303-313. 2. Bilge, S. S., C. R. Clausen, W. Lau, and S. L. Mosely. 1989. Molecular characterization of a fimbrial adhesin, F1845, mediating diffuse adherence of diarrhea-associated Escherichia coli to HEp-1 cells. J. Bacteriol. 171:4281-4289. 3. Brocteur, J., C. Francois-Gerard, A. Antre, M. Radermecker, M. Bruwier, and J. Salmon. 1975. Immunization against avian proteins. Haematologia 9:43-47. 4. de Man, P., B. Cedergren, S. Enerback, A.-C. Larsson, H. Leffler, A.-L. Lundell, B. Nilsson, and C. Svanborg-Ed6n. 1987. Receptor-specific agglutination tests for detection of bacteria that bind globoseries glycolipids. J. Clin. Microbiol. 25:401-406. 5. Duguid, J. P., I. W. Smith, G. Dempster, and P. N. Edmunds. 1955. Nonflagellar filamentous appendages ("fimbriae") and haemagglutinating activity in Bactenium coli. J. Pathol. Bacteriol. 70:335-349. 6. Ekback, G., S. Morner, B. Lund, and S. NormarL 1986. Correlation of genes in the pap gene cluster to expression of globoside-specific adhesin by uropathogenic Escherichia coli. FEMS Microbiol. Lett. 34:355-360. 7. Enerbick, A., A.-C. Larsson, H. LeMer, A. Lundell, P. de Man, B. Nilsson, and C. Svanborg-Ed6n. 1987. Binding to galactose al-+4galactosep-containing receptors as potential diagnostic tool in urinary tract infection. J. Clin. Microbiol. 25:407-411. 8. Francois-Gerard, C., J. Brockteur, and A. Andre. 1980. Turtledove: a new source of P1-like material cross-reacting with the human erythrocyte antigen. Vox Sang. 39:141-148. 9. Francois-Gerard, C., C. Gerday, and J. G. Beeley. 1979. Turtledove ovomucoid, a glycoprotein proteinase inhibitor with P1blood-group antigen activity. Biochem. J. 177:679-685. 10. Hacker, J., G. Schmidt, C. Hughes, S. Knapp, M. Marget, and W. Goebel. 1985. Cloning and characterization of genes involved in production of mannose-resistant, neuraminidase-susceptible (X) fimbriae from a uropathogenic 06:K15:H31 Escherichia coli strain. Infect. Immun. 47:434-440. 11. Hagberg, L., H. Leffler, and C. Svanborg Eden. 1985. Nonantibiotic prevention of urinary tract infection. Infection 13(Suppl.): S196-S200. 12. Hull, R. A., R. E. Gill, P. Hsu, B. H. Minshew, and S. Falkow. 1981. Construction and expression of recombinant plasmids encoding type 1 or D-mannose-resistant pili from a urinary tract infection Escherichia coli isolate. Infect. Immun. 33:933-938. 13. Inglis, G., A. G. Watt, and A. C. Munro. 1982. The production of anti-P1 in rabbits immunized with pigeon ovomucoid. Med. Lab. Sci. 39:179-181. 14. Johnson, J. R. 1991. Virulence factors in Escherichia coli urinary tract infection. Clin. Microbiol. Rev. 4:80-128. 15. Johnson, J. R., and T. Berggren. Pigeon and dove eggwhite protect mice against renal infection due to P-fimbriated Escherichia coli. Am. J. Med. Sci., in press. 16. Johnson, J. R., T. Berggren, D. S. Newburg, R. H. McCluer, and

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than other P adhesins (14), its coding sequence, primary structure, and receptor binding specificities are distinct from those of most other P adhesins (6, 31, 41), leaving in question the applicability to wild-type P adhesins of findings relative to the J96 P adhesin. Our results suggest that avian P1-antigen-containing products could be used in defining the P- and NPMR-adhesin phenotype of clinical isolates, which would help laboratories with limited budgets for synthetic oligosaccharides and without access to p erythrocytes. A recent report from Kunin et al. demonstrates the utility of this approach (26). Compared with results from agglutination testing done on ice, we found the performance characteristics for MRHA inhibition by DEW or PEW as a test for P adhesins to be as follows: sensitivity, 1.00; specificity, 0.67; positive predictive value, 0.95; and negative predictive value, 1.00. Conversely, the performance characteristics of MRHA resistance to DEW or PEW as a test for NPMR adhesins were as follows: sensitivity, 0.67; specificity, 1.00; positive predictive value, 1.00; and negative predictive value, 0.95. Others have protected animals from experimental ascending urinary tract infection (22, 42, 43) using P-adhesin receptor analogs that are too expensive for clinical use (19). We previously showed that DEW and PEW also can be used in this role (15). In our earlier study (15), female BALB/c mice were challenged with ca. 5.0 x 109 CFU of strain H5, a nephropathogenic (16) globoside-resistant P-fimbriated strain included in the present study. Bacteria were suspended in saline alone, saline plus D-mannose (MAN), or MAN plus CEW, DEW, PEW, or globoside. At 24 h, only 15% of kidneys from DEW or PEW recipients were culture positive, compared with 33% from PBS recipients, 40% from MAN recipients, 30% from globoside recipients, and 25% from CEW recipients (P < 0.05 for DEW and PEW versus PBS, MAN, and globoside) (15). The mean renal colony count also was significantly lower (P < 0.05) among DEW or PEW recipients than among recipients of PBS, MAN, globoside, or CEW (15). Taken together with these findings involving strain H5, the results of the present study suggest that avian P-adhesin inhibitors may be able to protect against upper urinary tract infections due to most wild-type P-fimbriated strains. That globoside fully inhibited P adhesins for only a minority of our strains was surprising, considering our previous findings with the J96 P adhesin (18) and globoside's reported efficacy in blocking E. coli adherence to human uroepithelial cells (22, 23, 27, 28) and erythrocytes (35). Paradoxically, we found that even globoside-resistant P-fimbriated strains readily agglutinated globoside-coated p erythrocytes. Our observations could be explained by a model in which the lipid portion of globoside binds to hydrophobic regions on particles while the Gal-Gal oligosaccharide portion interacts with P adhesins. The globoside molecule thus forms a bridge connecting bacterial adhesins to agglutinable particles, enhancing rather than inhibiting agglutination (11). Agglutination experiments involving globoside-coated P beads, p erythrocytes, and bacterial cells supported such a model. We found that agglutination tests done on ice were superior to room-temperature tests in defining adhesin phenotypes, whereas room-temperature tests were simpler. Duguid et al. originally described the temperature dependence of E. coli-mediated hemagglutination (5). Some contemporary investigators have done MRHA assays at room temperature (1, 4, 20, 34, 39, 44, 45); others have done such assays in the cold (7, 29, 32, 36, 37, 46). The influence of

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NOTES