| Summary: | 博士 === 國立成功大學 === 臨床醫學研究所 === 93 === Background: Upper urinary tract infection (UTI) is one of the major causes of morbidity and mortality for human. Escherichia coli is the most common pathogen for upper UTI. The putative virulence factors of E. coli include P-fimbriae, hemolysin and aerobactin; and the P-fimbriae is most frequently associated with upper UTI. The PapG adhesins at the tip of P-fimbriae mediate the binding with receptors on the uroepithelial cells. Recent studies have shown there are three variants of PapG adhesins. However, the roles of PapG adhesins subtypes, other fimbrial or non-fimbrial adhesins and toxins of E. coli in the development of upper UTI (i.e. acute renal infection ) are still unclear. In addition, only rare studies have examined these virulence factors concurrently with host factors that also may contribute to renal infection. Emphysematous pyelonephritis (EPN) is the most severe form of upper UTI. We have published a study on the clinical manifestations, radiological classification, pathogenesis, and outcome of EPN in “Archives of Internal Medicine”. However, there has been no control study of investigating the host and bacterial factors predisposing to the development of EPN and, thus, the precise pathogenesis remains obscure.
Aims: (1) to identify the host and E. coli virulence factors associated with upper UTI; (2) to investigate the interaction between host and E. coli virulence factors in upper UTI; (3) to investigate the association between P-fimbrial adhesin II (PapG II) and upper UTI; (4) to determine the role of PapG II adhesin in the development of upper UTI; (5) to identify the host and bacterial factors predisposing to the development of EPN.
Materials and Methods: Patients who fulfilled the diagnostic criteria for upper or lower UTI caused by E. coli were enrolled into this study. Availability of a stock of causative E. coli is prerequisite for inclusion. The prevalence of host factors and E. coli virulence factors was compared between lower and upper UTI groups. The prevalence of potential virulence genes of E. coli isolate was determined by polymerase chain reaction (PCR) method. To determine the importance of the papG II gene in the development of upper UTI, we constructed an isogenic mutant, deficient in PapG II adhesin phenotype, and compared the phenotypes of this mutant with its parental strain, a clinical isolate from a pyelonephritis patients, including its colonization ability in kidney in the ascending UTI model of BALB/c mouse. For investigation of the pathogenesis of EPN, we identified the host and bacterial factors by comparing with analogs in non-gas-forming renal infections (i.e. non-EPN) and determined the role of bacterial gas-producing capacity by comparison for the gas volumes produced by EPN and non-EPN E. coli strains, cultured in broths with different glucose concentrations.
Results: Diabetes with poor blood glucose control, immunosuppression, urinary tract obstruction, and papG II gene were independently associated with upper UTI. However, the papG II gene was less prevalent in strains isolated from patients with upper UTI with urinary tract obstruction or with two of the three predisposing host factors. The results of ascending BALB/c mice model of renal infection showed that the geometric means of quantitative bacterial counts in mice kidney were significantly decreased when challenged with mutant strain, which was mutated in the papG II gene, than with wild type strain on day 3 after inoculation, at both low and high inoculation dose (P < 0.05). The results of EPN pathogensis showed diabetic mellitus with poor glycemic control (i.e. HbA1C level > 11%) was the only host factor independently associated with EPN. Higher prevalence of the iroN and usp genes was demonstrated in the EPN strains. The gas volumes produced by E. coli were significantly increased only when the glucose concentrations of broths were elevated to 250 mg/dl in both groups.
Conclusion: This study contributes to a further understanding of the roles of hosts and bacterial factors in the pathogenesis of upper UTI and EPN. It demonstrated that both the hosts and bacterial factors can contribute to the development of upper UTI, and less virulent strains can cause upper UTI in hosts with predisposing factors. The papG II gene plays an important role in the development of upper UTI, and blocking the normal expression of papG II gene by mutation can inhibit the early establishment of E. coli in the kidney. Diabetes mellitus with poor glycemic control, major urinary tract obstruction, and more virulent strain are the factors predisposing to EPN.
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