THE JOURNAL OF INFECTIOUS DISEASES. VOL. 137, NO.5. MAY 1978 © 1978 by the University of Chicago. 0022-1899178/3705-0004$00.75
Factors Affecting Virulence in Escherichia coli Urinary Tract Infections John Z. Montgomerie
From the Department of Medicine, Rancho Los Amigos Hospital, and The University of Southern California, School of Medicine, Los Angeles, California
involvement possessed K antigens more frequently than those strains taken from patients whose infections were confined to the bladder. The K antigen was also found more often, and in greater amounts, in E. coli taken from the urine of children with pyelonephritis than in strains taken from children with cystitis or from stools of healthy schoolchildren [9]. The mechanism by which K antigen promotes virulence is uncertain, but it may be related to an organism's ability to resist phagocytosis and the bactericidal activity of serum [10]. The bacterial strains responsible for urinary tract infections have been found to possess increased resistance to the normal bactericidal activity of serum [11]. Strains of E. coli (sera types 1, 4, 6, and 75) that were prevalent in patients with bacteriuria were also more resistant to serum bactericidal activity than other, less prevalent strains of E. coli. A number of other studies have suggested a possible correlation between the virulence of an organism and the ability of that organism to adhere to the surface of an organ. This abili ty to adhere to surfaces has, in some instances, been correlated with the presence of pili (fimbriae) or other surface factors on the organism. The evidence capable of demonstrating that this adherence is an important virulence factor in the urinary tract is, at the present time, limited. Eden et a1. [12J found that the ability of E. coli to become attached to epithelial cells from the urinary tract was much greater in strains of E. coli isolated from the urine of patients with acute pyelonephritis or cystitis than it was in those strains isolated from the urine of patients with asymptomatic bacteriuria. Silverblatt [13J described a pathogenic role of pili in Proteus mirabilis infections of the kidney in rats. In recent years we have examined some factors influencing the pathogenicity of 22 strains of E. coli as part of a study of ascending pyelonephritis in mice (table 1) [14J. A model of urinary
Factors Contributing to Virulence
Early observations seemed to indicate that the majority of strains of E. coli isolated from the urinary tract belonged to relatively few 0 serotypes [1, 2]. This indication, in turn, suggested that these serotypes might be more invasive for the urinary tract than others. Turck and Petersdod [3J, however, concluded that infections by these strains of E. coli were more common because they were more prevalent in the bowel. This finding has been supported by other studies [4-6]. There have, on the other hand, also been studies in which one or two serotypes were found to be more prevalent in the urine than in the bowel [7]. Serotypes 1, 4, 6, 50, and 75 are those most frequently found in the urinary tract and bowel flora. Note, however, that these serotypes vary in different medical centers, a reflection of population differences. The capsule also plays an important part in the virulence of many bacteria. The capsular antigen of E. coli, i.e., K antigen, has been associated with the ability of E. coli to produce pyelonephritis. Glynn et a1. [8J found that strains of E. coli taken from infected patients with renal Please address requests for reprints to Dr. John Montgomerie, Rancho Los Amigos Hospital, Division of Infectious Diseases, Room 239, 7601 Imperial Highway. Downey. California 90242.
645
Downloaded from http://jid.oxfordjournals.org/ at Indiana University Library on July 13, 2015
The prevalence of Escherichia coli in infections of the urinary tract is assumed to result from its proximity to the gastrointestinal tract. There are certain characteristics of the E. coli species that have been related to the greater virulence of one particular strain over that of another. The following is a brief review of the virulence factors of E. coli that have been examined in clinical and experimental studies of urinary tract infection.
Montgomerie
646
Table 1. Factors influencing the pathogenicity of Escherichia coli in pyelonephritis. Measure of virulence * Factor
*A
+ + + +
Proportion of deaths +
+
+ +
plus sign indicates significance at a confidence level of minus sign indicates not significant.
~O.05. A
tract infection had been developed by Keane and Freedman [15]. The virulence of the E. coli in the urinary tract was measured by the ability of the E. coli injected into the bladder to produce renal infection and by their ability to produce death of the mice. When deaths occurred, the majority of which were within 24 hr of inoculation, the early deaths were assumed to be due to endotoxin. The ability of E. coli to produce infection in the kidney correlated with the presence of K antigen, resistance to phagocytosis and serum bactericidal activity, dulcitol fermentation, and the ability to multiply in urine and minimal media. The ability of E. coli to infect the kidney was related positively to fermentation of dulcitol. This correlation has been confirmed in a more recent study [16], but there does not seem to be an explanation for this finding. Although we were unable to correlate motility of E. coli with nephropathogenicity, other workers have demonstrated a connection [17]. In that study, E. coli strains that produced a high rate of pyelonephritis did not necessarily produce a high rate of death. This failure to correlate virulence as measured by production of pyelonephritis with virulence as measured by proportion of deaths has been observed in previous studies [18, 19]. U sing the same strains of E. coli and the same model of urinary tract infection as were used in the experiments described above, we were also
Summary
The prevalence of E. coli relative to other bacteria in the urinary tract is assumed to be the result of its proximity to and its close relationship with the gastrointestinal tract. Strains of E. coli may establish themselves more readily in the urinary tract, and/or invade the upper urinary tract, if they have a number of different virulence factors. The relative importance of these factors in the development of urinary tract infection, with or without renal involvement, is not clear. In addi tion, the means by which these factors may increase the virulence of E. coli are not understood, although there seems to be some evidence that the K antigens alter resistance to phagocytosis and serum bactericidal activity [9, 10]. The main reason that certain E. coli serotypes are cultured from the urinary tract, however, still seems to be their dominance in the stool. The broader question of why certain 0 serotypes of E. coli dominate the bowel flora has not been examined adequately. The studies suggesting that the K antigen is a significant virulence factor seem to be in conflict with other studies indicating the dominance of certain serotypes of E. coli in the stool and in urinary tract infections. A resolution of this dilemma may possibly be found in the recent observations of Dr. Frits 0rskov [20] and others discussed elsewhere at this meeting that the K and o serotypes appear to be interrelated. References I. Kauffman, F. The serology of the coli group. J. Immunol. 57:71-100, 1947. 2. Rantz, L. A. Serological grouping of Escherichia coli. Arch. Intern. Med. 109:37-42, 1962. 3. Turck, M., Petersdorf, R. G. The epidemiology of nonenteric Escherichia coli infections: prevalence of serological groups. J. Clin. Invest. 41:1760-1765,1962. 4. Kennedy, R. P., Plorde, J. J., Petersdorf, R. G. Evidence for a nosocomial gram-negative "flora." In E. H. Kass [ed.]. Progress in pyelonephritis. Davis, Philadelphia, 1965, p. 193-201.
Downloaded from http://jid.oxfordjournals.org/ at Indiana University Library on July 13, 2015
Phagocytosis Growth in minimal media Growth in urine K antigen Serum bactericidal activity Dulcitol fermentation Rough mutation Motility Adherence to bladder epithelium Presence of pili Iron-binding catechols
Renal infection
unable to correlate virulence with adherence of the E. coli to bladder epithelial cells, the presence of pili, or with the presence of iron-binding catechols in E. coli (]. Montomerie, G. M. Kalmanson, and L. B. Guze, unpublished observations).
Virulence Factors in E. coli UTI
13. 14.
15.
16.
17. 18.
19.
20.
strains associated with various forms of urinary tract infection. Lancet 2:490--492, 1976. Silverblatt, F. J. Host-parasite interaction in the rat renal pelvis. J. Exp. Med. 140:1696-1711,1974. Guze, L. B., Montgomerie, J. Z., Potter, C. S., Kalmanson, G. M. Pyelonephritis. XVI. Correlates of parasite virulence in acute ascending Escherichia coli pyelonephritis in mice undergoing diuresis. Yale J. BioI Med. 46:203-211,1973. Keane, W. F., Freedman, L. R. Experimental pyelonephritis. XIV. Pyelonephritis in normal mice produced by inoculation of E. coli into the bladder lumen during water diuresis. Yale J. BioI. Med. 40: 231-237,1967. Kalmanson, G. M., Harwick, J. J., Turck, M., Guze, L. B. Urinary tract infection: localisation and virulence of Escherichia coli. Lancet 1:134-136, 1975. Pazin, G. J., Braude, A. I. Immobilizing antibodies in pyelonephritis. J. Immunol. 102:1454-1465, 1969. Brumfitt, W., Heptinstall, R. H. Experimental pyelonephritis: the relationship of bacterial virulence to the establishment of the renal lesion. J. Exp. Pathol. 41 :552-558, 1960. McCabe, W. R., Jackson, G. G. The natural course of retrograde infections of the urinary tract of rats with different serotypes of Escherichia coli and enterococcus. In E. L. Quinn and E. H. Kass [ed.]. Biology of pyelonephritis. Little, Brown, Boston, 1960, p. 39-52. Y)rskov, F. Virulence factors of the bacterial cell surface. J. Infect. Dis. 137:630-633,1978.
Downloaded from http://jid.oxfordjournals.org/ at Indiana University Library on July 13, 2015
5. Gruneberg, R. N., Leigh, D. A., Brumfitt, W. Escherichia coli serotypes in urinary tract infection: studies in domiciliary, ante-natal and hospital practice. In F. O'Grady and W. Brumfitt [ed.], Urinary tract infection. Oxford University Press, London, 1968, p. 68-79. 6. Vosti, K. L., Goldberg, L. M., Monto, A. S., Rantz, L. A. Host parasite interaction in patients with infections due to Escherichia coli. I. The serogrouping of E. coli from intestinal and extraintestinal sources. J. Clin. Invest. 43:2377-2385,1964. 7. Hanson, L. A. Host-parasite relationships in urinary tract infections. J. Infect. Dis. 127:726-730,1973. 8. Glynn, A. A., Brumfitt, W., Howard, C. J. K antigens of Escherichia coli and renal involvement in urinary tract infections. Lancet 1:514-519, 1971. 9. Kaijser, B. Immunology of Escherichia coli: K antigen and its relation to urinary-tract infection. J. Infect. Dis. 127:670-677, 1973. 10. Howard, C. J., Glynn, A. A. The virulence for mice of strains of Escherichia coli related to the effects of K antigens on their resistance to phagocytosis and killing by complement. Immunology 20:767-777, 1971. 11. Kimball, H., Garcia, M., Petersdorf, R. G. The epidemiology of nonenteric Escherichia coli infections. II. Relationship of prevalence of E. coli in urinary infections to the bactericidal effect of human serum. J. Lab. Clin. Med. 63:901-906,1964. 12. Eden, C. S., Jodal, U., Hanson, L. A., Lindberg, U., Akerlund, A. S. Variable adherence to normal human urinary tract epithelial cells of Escherichia coli
647
Factors Affecting Virulence in Escherichia coli Urinary Tract Infections John Z. Montgomerie
From the Department of Medicine, Rancho Los Amigos Hospital, and The University of Southern California, School of Medicine, Los Angeles, California
involvement possessed K antigens more frequently than those strains taken from patients whose infections were confined to the bladder. The K antigen was also found more often, and in greater amounts, in E. coli taken from the urine of children with pyelonephritis than in strains taken from children with cystitis or from stools of healthy schoolchildren [9]. The mechanism by which K antigen promotes virulence is uncertain, but it may be related to an organism's ability to resist phagocytosis and the bactericidal activity of serum [10]. The bacterial strains responsible for urinary tract infections have been found to possess increased resistance to the normal bactericidal activity of serum [11]. Strains of E. coli (sera types 1, 4, 6, and 75) that were prevalent in patients with bacteriuria were also more resistant to serum bactericidal activity than other, less prevalent strains of E. coli. A number of other studies have suggested a possible correlation between the virulence of an organism and the ability of that organism to adhere to the surface of an organ. This abili ty to adhere to surfaces has, in some instances, been correlated with the presence of pili (fimbriae) or other surface factors on the organism. The evidence capable of demonstrating that this adherence is an important virulence factor in the urinary tract is, at the present time, limited. Eden et a1. [12J found that the ability of E. coli to become attached to epithelial cells from the urinary tract was much greater in strains of E. coli isolated from the urine of patients with acute pyelonephritis or cystitis than it was in those strains isolated from the urine of patients with asymptomatic bacteriuria. Silverblatt [13J described a pathogenic role of pili in Proteus mirabilis infections of the kidney in rats. In recent years we have examined some factors influencing the pathogenicity of 22 strains of E. coli as part of a study of ascending pyelonephritis in mice (table 1) [14J. A model of urinary
Factors Contributing to Virulence
Early observations seemed to indicate that the majority of strains of E. coli isolated from the urinary tract belonged to relatively few 0 serotypes [1, 2]. This indication, in turn, suggested that these serotypes might be more invasive for the urinary tract than others. Turck and Petersdod [3J, however, concluded that infections by these strains of E. coli were more common because they were more prevalent in the bowel. This finding has been supported by other studies [4-6]. There have, on the other hand, also been studies in which one or two serotypes were found to be more prevalent in the urine than in the bowel [7]. Serotypes 1, 4, 6, 50, and 75 are those most frequently found in the urinary tract and bowel flora. Note, however, that these serotypes vary in different medical centers, a reflection of population differences. The capsule also plays an important part in the virulence of many bacteria. The capsular antigen of E. coli, i.e., K antigen, has been associated with the ability of E. coli to produce pyelonephritis. Glynn et a1. [8J found that strains of E. coli taken from infected patients with renal Please address requests for reprints to Dr. John Montgomerie, Rancho Los Amigos Hospital, Division of Infectious Diseases, Room 239, 7601 Imperial Highway. Downey. California 90242.
645
Downloaded from http://jid.oxfordjournals.org/ at Indiana University Library on July 13, 2015
The prevalence of Escherichia coli in infections of the urinary tract is assumed to result from its proximity to the gastrointestinal tract. There are certain characteristics of the E. coli species that have been related to the greater virulence of one particular strain over that of another. The following is a brief review of the virulence factors of E. coli that have been examined in clinical and experimental studies of urinary tract infection.
Montgomerie
646
Table 1. Factors influencing the pathogenicity of Escherichia coli in pyelonephritis. Measure of virulence * Factor
*A
+ + + +
Proportion of deaths +
+
+ +
plus sign indicates significance at a confidence level of minus sign indicates not significant.
~O.05. A
tract infection had been developed by Keane and Freedman [15]. The virulence of the E. coli in the urinary tract was measured by the ability of the E. coli injected into the bladder to produce renal infection and by their ability to produce death of the mice. When deaths occurred, the majority of which were within 24 hr of inoculation, the early deaths were assumed to be due to endotoxin. The ability of E. coli to produce infection in the kidney correlated with the presence of K antigen, resistance to phagocytosis and serum bactericidal activity, dulcitol fermentation, and the ability to multiply in urine and minimal media. The ability of E. coli to infect the kidney was related positively to fermentation of dulcitol. This correlation has been confirmed in a more recent study [16], but there does not seem to be an explanation for this finding. Although we were unable to correlate motility of E. coli with nephropathogenicity, other workers have demonstrated a connection [17]. In that study, E. coli strains that produced a high rate of pyelonephritis did not necessarily produce a high rate of death. This failure to correlate virulence as measured by production of pyelonephritis with virulence as measured by proportion of deaths has been observed in previous studies [18, 19]. U sing the same strains of E. coli and the same model of urinary tract infection as were used in the experiments described above, we were also
Summary
The prevalence of E. coli relative to other bacteria in the urinary tract is assumed to be the result of its proximity to and its close relationship with the gastrointestinal tract. Strains of E. coli may establish themselves more readily in the urinary tract, and/or invade the upper urinary tract, if they have a number of different virulence factors. The relative importance of these factors in the development of urinary tract infection, with or without renal involvement, is not clear. In addi tion, the means by which these factors may increase the virulence of E. coli are not understood, although there seems to be some evidence that the K antigens alter resistance to phagocytosis and serum bactericidal activity [9, 10]. The main reason that certain E. coli serotypes are cultured from the urinary tract, however, still seems to be their dominance in the stool. The broader question of why certain 0 serotypes of E. coli dominate the bowel flora has not been examined adequately. The studies suggesting that the K antigen is a significant virulence factor seem to be in conflict with other studies indicating the dominance of certain serotypes of E. coli in the stool and in urinary tract infections. A resolution of this dilemma may possibly be found in the recent observations of Dr. Frits 0rskov [20] and others discussed elsewhere at this meeting that the K and o serotypes appear to be interrelated. References I. Kauffman, F. The serology of the coli group. J. Immunol. 57:71-100, 1947. 2. Rantz, L. A. Serological grouping of Escherichia coli. Arch. Intern. Med. 109:37-42, 1962. 3. Turck, M., Petersdorf, R. G. The epidemiology of nonenteric Escherichia coli infections: prevalence of serological groups. J. Clin. Invest. 41:1760-1765,1962. 4. Kennedy, R. P., Plorde, J. J., Petersdorf, R. G. Evidence for a nosocomial gram-negative "flora." In E. H. Kass [ed.]. Progress in pyelonephritis. Davis, Philadelphia, 1965, p. 193-201.
Downloaded from http://jid.oxfordjournals.org/ at Indiana University Library on July 13, 2015
Phagocytosis Growth in minimal media Growth in urine K antigen Serum bactericidal activity Dulcitol fermentation Rough mutation Motility Adherence to bladder epithelium Presence of pili Iron-binding catechols
Renal infection
unable to correlate virulence with adherence of the E. coli to bladder epithelial cells, the presence of pili, or with the presence of iron-binding catechols in E. coli (]. Montomerie, G. M. Kalmanson, and L. B. Guze, unpublished observations).
Virulence Factors in E. coli UTI
13. 14.
15.
16.
17. 18.
19.
20.
strains associated with various forms of urinary tract infection. Lancet 2:490--492, 1976. Silverblatt, F. J. Host-parasite interaction in the rat renal pelvis. J. Exp. Med. 140:1696-1711,1974. Guze, L. B., Montgomerie, J. Z., Potter, C. S., Kalmanson, G. M. Pyelonephritis. XVI. Correlates of parasite virulence in acute ascending Escherichia coli pyelonephritis in mice undergoing diuresis. Yale J. BioI Med. 46:203-211,1973. Keane, W. F., Freedman, L. R. Experimental pyelonephritis. XIV. Pyelonephritis in normal mice produced by inoculation of E. coli into the bladder lumen during water diuresis. Yale J. BioI. Med. 40: 231-237,1967. Kalmanson, G. M., Harwick, J. J., Turck, M., Guze, L. B. Urinary tract infection: localisation and virulence of Escherichia coli. Lancet 1:134-136, 1975. Pazin, G. J., Braude, A. I. Immobilizing antibodies in pyelonephritis. J. Immunol. 102:1454-1465, 1969. Brumfitt, W., Heptinstall, R. H. Experimental pyelonephritis: the relationship of bacterial virulence to the establishment of the renal lesion. J. Exp. Pathol. 41 :552-558, 1960. McCabe, W. R., Jackson, G. G. The natural course of retrograde infections of the urinary tract of rats with different serotypes of Escherichia coli and enterococcus. In E. L. Quinn and E. H. Kass [ed.]. Biology of pyelonephritis. Little, Brown, Boston, 1960, p. 39-52. Y)rskov, F. Virulence factors of the bacterial cell surface. J. Infect. Dis. 137:630-633,1978.
Downloaded from http://jid.oxfordjournals.org/ at Indiana University Library on July 13, 2015
5. Gruneberg, R. N., Leigh, D. A., Brumfitt, W. Escherichia coli serotypes in urinary tract infection: studies in domiciliary, ante-natal and hospital practice. In F. O'Grady and W. Brumfitt [ed.], Urinary tract infection. Oxford University Press, London, 1968, p. 68-79. 6. Vosti, K. L., Goldberg, L. M., Monto, A. S., Rantz, L. A. Host parasite interaction in patients with infections due to Escherichia coli. I. The serogrouping of E. coli from intestinal and extraintestinal sources. J. Clin. Invest. 43:2377-2385,1964. 7. Hanson, L. A. Host-parasite relationships in urinary tract infections. J. Infect. Dis. 127:726-730,1973. 8. Glynn, A. A., Brumfitt, W., Howard, C. J. K antigens of Escherichia coli and renal involvement in urinary tract infections. Lancet 1:514-519, 1971. 9. Kaijser, B. Immunology of Escherichia coli: K antigen and its relation to urinary-tract infection. J. Infect. Dis. 127:670-677, 1973. 10. Howard, C. J., Glynn, A. A. The virulence for mice of strains of Escherichia coli related to the effects of K antigens on their resistance to phagocytosis and killing by complement. Immunology 20:767-777, 1971. 11. Kimball, H., Garcia, M., Petersdorf, R. G. The epidemiology of nonenteric Escherichia coli infections. II. Relationship of prevalence of E. coli in urinary infections to the bactericidal effect of human serum. J. Lab. Clin. Med. 63:901-906,1964. 12. Eden, C. S., Jodal, U., Hanson, L. A., Lindberg, U., Akerlund, A. S. Variable adherence to normal human urinary tract epithelial cells of Escherichia coli
647
