FIMH ADHESIN VACCINES TO PREVENT URINARY TRACT INFECTION

细菌附着于寄主上皮是一个重要的早期事件

Bacterial attachment to host epithelium is an important early event in the pathogenesis of Escherichia coli urinary tract infections. This attachment is mediated by adhesin proteins that are associated with heteropolymeric fiber-like structures on the bacterial surface, called pili. The identification of tip adhesins at the distal end of pili provides an important novel target for vaccine development as early attempts to use whole pili were not successful in protecting against a broad range of pathogenic bacterial isolates. Uropathogenic E.coli are capable of producing a variety of adhesins as well as pilus types, which confer host cell receptor specifically to the pathogens. These structures dictate the tissue tropism, sites of colonization within the urogenital tract, and the resultant diseases that ensue from infection. The FimH adhesin which is associated with the type l -pilus binds to alpha-D-mannoside glycoconjugates which are abundant on bladder epithelium. Epidemiological and experimental evidence supports a role for type l -piliated E.coli in the development of cystitis. We have recently found that antibody raised specifically against two forms of the purified FimH adhesin prevents type l -piliated E.coli from binding to a- D-mannoside receptors, as measured by inhibition of agglutination of guinea pig erythrocytes and blocking of attachment by type l -piliated E.coli to human bladder cells in vitro. Furthermore, both the FimH-derived vaccines resulted in reduced colonization of the bladder by uropathogenic isolates of type l-piliated E.coli in vivo in murine cystitis model. These data suggest that anti-bacterial vaccines targeting adhesins may block attachment in vivo, and may be a means of preventing recurrent and acute urinary tract infections. Our objectives in this study are: 1.) to evaluate a third FimH-based vaccine candidate, type l tip fibrillae, which should induce maximal protective immunity, targeted to the binding domain of this lectin based on the conformation of FimH in this complex, 2.) to assay the best candidate FimH vaccine among the three with a number of adjuvants including alum, MF-59 and rBCG to determine which adjuvant stimulates the best functional immune response as measured both in vitro and in vivo, and 3.) to test antisera raised against the best candidate FimH vaccine for in vitro functional activity against a wide range of primary uropathogenic E.coli clinical isolates. PROPOSED COMMERCIAL APPLICATION: These studies may lead to the development of a vaccine against bacterial urinary tract infections, one of the most common disorders prompting medical attention. The mucosal adjuvants being tested may stimulate mucosal as well as humoral immune responses against uropatheogenic bacteria.