Escherichia coli, fimbriae, bacterial persistence and host response induction in the human urinary tract.

Urinary tract infections (UTI) are among the most common bacterial infections in humans. Symptomatic UTIs may be acute, recurrent or chronic but the most frequent form of UTI is asymptomatic bacteruria (ABU). In ABU, the mucosa remains inert, despite the presence of large bacterial numbers in urine. The difference in disease severity reflects the virulence of the infecting strain and the propensity of the host to respond to infection. It is essential to understand the molecular basis of disease diversity and the molecular interactions between bacteria and host that determine asymptomatic carriage and the transition to disease. We discuss the initial interactions between bacteria and the mucosal surfaces in the human urinary tract, and the bacterial factors involved in the breach of mucosal inertia. Specifically, the contribution of P and type 1 fimbriae to bacterial establishment and host response induction are investigated. The results show that P fimbriae serve as independent virulence factors when expressed by an ABU strain, by promoting the establishment of bacteriuria and the innate host response, which is the cause of symptoms and tissue damage. P fimbriae thus fulfil the molecular Koch postulates as independent virulence factors in the human urinary tract. Type 1 fimbriae, in contrast, did not act as virulence factors in this model, and thus appear to serve a different function in man than in the murine model.

Bergsten G ，Wullt B ，Svanborg C 《INTERNATIONAL JOURNAL OF MEDICAL MICROBIOLOGY》

The role of P fimbriae for Escherichia coli establishment and mucosal inflammation in the human urinary tract.

Bacterial adhesion to the bladder mucosa is a critical step for the establishment of Escherichia coli bacteriuria. The P-fimbriae, encoded by the pap gene cluster, are considered as virulence factors but the mechanisms have been debated. This study defined the roles for P fimbriation during the early colonization of the human urinary tract. Patients with recurrent UTI were first subjected to deliberate colonization with the non-fimbriated ABU strain E. coli 83972. Bacteriuria was established long term (1-4 years) in patients with dysfunctional bladders, but not in the patients with normal bladder function. Super-infections were transient and asymptomatic. P fimbriated transformants of the ABU strain (E. coli 83972pap+/prs+) reached 105 CFU/ml more rapidly than E. coli 83972 and the vector control. This was demonstrated by group wise and intra-individual analysis in patients colonized on different occasions with E. coli 83972 or the P fimbriated transformants. Higher neutrophil numbers and IL-8 and IL-6 concentrations in urine were obtained after colonization with the P fimbriated transformants. These results demonstrated that transformation of E. coli 83972 with the pap sequences is sufficient to convert it to a more potent host response inducer. The P fimbriae were shown to lower the significant bacteriuria threshold. The P fimbriated transformants needed lower bacterial numbers (103-4 CFU/ml) to predict a positive second urine culture with a >80% accuracy and to trigger a significant host response. These studies show that P fimbriae fulfil the Koch Henles molecular postulates for bacterial establishment and host response induction in the human urinary tract.

Wullt B 《INTERNATIONAL JOURNAL OF ANTIMICROBIAL AGENTS》

Do type 1 fimbriae promote inflammation in the human urinary tract?

Type 1 fimbriae have been implicated as virulence factors in animal models of urinary tract infection (UTI), but the function in human disease remains unclear. This study used a human challenge model to examine if type 1 fimbriae trigger inflammation in the urinary tract. The asymptomatic bacteriuria strain Escherichia coli 83972, which fails to express type 1 fimbriae, due to a 4.25 kb fimB-fimD deletion, was reconstituted with a functional fim gene cluster and fimbrial expression was monitored through a gfp reporter. Each patient was inoculated with the fim+ or fim- variants on separate occasions, and the host response to type 1 fimbriae was quantified by intraindividual comparisons of the responses to the fim+ or fim- isogens, using cytokines and neutrophils as end-points. Type 1 fimbriae did not promote inflammation and adherence was poor, as examined on exfoliated cells in urine. This was unexpected, as type 1 fimbriae enhanced the inflammatory response to the same strain in the murine urinary tract and as P fimbrial expression by E. coli 83972 enhances adherence and inflammation in challenged patients. We conclude that type 1 fimbriae do not contribute to the mucosal inflammatory response in the human urinary tract.

Bergsten G ，Wullt B ，Schembri MA ，Leijonhufvud I ，Svanborg C ... -  《CELLULAR MICROBIOLOGY》

Asymptomatic bacteriuria Escherichia coli strains: adhesins, growth and competition.

Urinary tract infections (UTIs) affect millions of people each year. Escherichia coli is the most common organism associated with asymptomatic bacteriuria (ABU) in humans. Persons affected by ABU may carry a particular E. coli strain for extended periods of time without any symptoms. In contrast to uropathogenic E. coli (UPEC) that cause symptomatic UTI, very little is known about the mechanisms by which these strains colonize the urinary tract. Here, we have investigated the growth characteristics in human urine as well as adhesin repertoire of nine ABU strains; the ability of ABU strains to compete against the UPEC strain CFT073 was also studied. The different ABU strains displayed a wide variety of the measured characteristics. Half of the ABU strains displayed functional type 1 fimbriae while only one expressed functional P fimbriae. A good correlation between the growth rate of a particular strain and the survival of the strain in competition against CFT073 was observed. Our results support the notion that for strains with reduced capacity to express fimbriae, the ability to grow fast in human urine becomes crucial for colonization of the urinary tract.

Roos V ，Nielsen EM ，Klemm P 《FEMS MICROBIOLOGY LETTERS》

The role of P fimbriae for colonization and host response induction in the human urinary tract.

Wullt B ，Bergsten G ，Samuelsson M ，Gebretsadik N ，Hull R ，Svanborg C ... -  《JOURNAL OF INFECTIOUS DISEASES》