May 24, 2006 Scientists now have inside information to use in the fight against Proteus mirabilis -- a nasty bacterium that can cause kidney stones, as well as hard-to-treat urinary tract infections.
Data from the first complete genome sequence for P. mirabilis, which includes at least 3,693 genes and 4.063 megabases of DNA, will be presented at the 106th general meeting of the American Society of Microbiology taking place in Orlando from May 21-25.
Melanie M. Pearson, Ph.D., a research fellow in microbiology and immunology at the University of Michigan Medical School, is the first scientist to perform an in-depth analysis of the genome sequence. She will present her initial findings in an ASM poster presentation beginning at 9 a.m. on May 23.
"Access to the full genome sequence will help scientists determine the virulence factors produced by the organism and learn how it causes disease," Pearson says. "Part of our goal is finding potential targets for new vaccines that could protect people from infection."
"E. coli causes urinary tract infections in otherwise healthy individuals, but P. mirabilis causes more infections in those with 'complicated' urinary tracts. In cases where stones form, the bacteria can become resistant to antibiotics," says Harry L.T. Mobley, Ph.D., professor and chair of microbiology and immunology in the U-M Medical School. "It is particularly prevalent in nursing home residents with indwelling catheters."
Mobley is an expert on urease, an enzyme produced by P. mirabilis, which breaks down urea in the urinary tract, reduces the acidity of urine and leads to the formation of kidney or bladder stones. Once a stone begins to form, bacteria stick to the stone and live within its layers, where they are protected from antibiotics.
When Pearson examined the genomic sequence data for Proteus mirabilis, she discovered an explanation for the bacterium's "stickiness."
"This bacterium has an unusually high number of genes that encode for 15 different adherence factors or fimbriae on its surface," Pearson explains. "All these different fimbriae help the bacterium stick to bladder cells, catheters, kidney stones or each other.
It's not unusual for bacteria to have several ways of attaching to surfaces, but I've never heard of one with 15 different adherence factors before."
"Over the course of 20-plus years of laboratory research, we had painstakingly identified four P. mirabilis fimbriae," says Mobley. "Suddenly, here were 11 more predicted in the genome sequence data. We couldn't believe it."
Pearson also discovered what she calls a "pathogenicity island" in the P. mirabilis genome made up of 24 genes that encode components of a system used to inject bacterial proteins into host cells.
"Until we reviewed the sequence data, we had no idea P. mirabilis had these genes," Mobley says. "When Melanie analyzed the sequences of these 24 genes, she noticed that they have smaller amounts of two of the four nucleotides in DNA -- guanine and cytosine -- than are present in the overall genome. This implies that another bacterium contributed this little piece of DNA to P. mirabilis at some point during its evolution."
In future research, Pearson will use gene microarrays to identify the Proteus mirabilis genes that are turned on, or expressed, during the infection stage. Genes involved in the infection process will be prime targets for future vaccine development, according to Pearson, although she says that years of additional research will be needed before vaccines could be commercially available.
Mohammed Sebaihia and Julian Parkhill, scientists at the Wellcome Trust Sanger Institute in Cambridge, UK, were responsible for the sequencing process. The sequenced strain was P. mirabilis HI4320, a strain commonly used in laboratory research, which was cultured in the Mobley laboratory from the urine of a nursing home patient with a long-term indwelling catheter.
The research was supported by the National Institute of Diabetes and Digestive and Kidney Diseases, in collaboration with the Sanger Institute.
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