St. Louis, Oct.24, 2001 — Scientists at Washington University School of Medicine in St. Louis have mapped and sequenced the genome for a bacterium that is a leading cause of food poisoning worldwide: Salmonella typhimurium. The sequence has yielded new potential targets for future drug and vaccine development and gives possible insights into how the bacterium causes disease. The work is published in the Oct. 25 issue of the journal Nature.
Typhimurium infects humans, cattle, chickens, and other warm-blooded animals. The rod-shaped bacterium is important in bacterial-genetics research, and disabled strains are used in live vaccines and to deliver anti-cancer drugs to tumor cells. It also causes a typhoid-fever-like illness in mice that is used as a model for studies related to human typhoid fever. Typhimurium is thought to be responsible for an estimated 1.4 million cases of food poisoning in the United States each year, and about a 1,000 deaths. The intestinal illness usually resolves on its own, but sometimes the bacterium enters the bloodstream causing an infection that may be fatal if not treated with antibiotics. But that is becoming increasingly difficult.
“Antibiotic resistance is a growing problem in Typhimurium,” says principal investigator Richard Wilson, Ph.D., associate professor of genetics and co-director of the Genome Sequencing Center at the School of Medicine. “Ideally, we hope this work will identify possible new drug targets and reduce the threat of ever-more resistant strains of the bacterium.”
In addition to researchers at Washington University, the Typhimurium team included investigators at the Sidney Kimmel Cancer Center in San Diego; the University of Calgary in Alberta, Canada; and Pennsylvania State University.
The investigators identified 4,595 suspected genes in the Typhimurium genome, many of which were previously unknown. They include 156 probable membrane proteins that are potential drug or vaccine targets.
The researchers also found two previously unknown gene clusters required for producing the hair-like strands, or fimbriae, that cover the bacteria. The strands enable the bacterium to cling to cells that line the intestines. “These are also targets for potential therapies that might prevent the bacterium from attaching in the gut and thereby preclude infection,” says Sandra Clifton, Ph.D., research instructor in the Department of Genetics at Washington University and group leader for the project.
The investigators also compared the genome of Typhimurium to several closely related bacteria. The comparison revealed, for example, that Typhimurium contains a series of mostly previously unknown genes that are missing from subspecies of Salmonella that infect cold-blooded animals. “Those genes may enable Typhimurium to infect warm-blooded hosts,” says Clifton. The group worked closely with a team of researchers who were sequencing the genome for the subspecies of Salmonella that causes typhoid fever in humans, Salmonella typhi. A comparison of those two genomes revealed that the typhoid-causing Salmonella had more than 200 pseudogenes, genes that may be disabled and unused by the organism. Typhimurium, on the other hand, has only 39 pseudogenes. More work is needed to evaluate the loss of function of the pseudogenes. “These are only a few examples of information that can be gleaned from genomic sequences,” says Clifton. “Now the data are available to microbiologists to explore, to prove that a particular gene functions as we suspect it might or that a segment we suspect codes for a gene truly is a gene.”
The Typhimurium paper and the paper describing the genome for the typhoid fever bacterium are published as companion pieces in the same issue of Nature.
McClelland M, Sanderson KE, Spieth J, Clifton SW, Latreille P, Courtney L, Porwollik S, Ali J, Dante M, Du F, Hou S, Layman D, Leonard S, Nguyen C, Scott K, Holmes A, Grewal N, Mulvaney E, Ryan E, Sun H, Florea L, Miller W, Stoneking T, Nhan M, Waterston R, Wilson RK. The complete genome sequence of Salmonella enterica serovar S. Typhimurium LT2. Nature, Vol. 413, 852-856, Oct. 25, 2001.
This research was supported by grants from the National Institute of Allergy and Infectious Diseases.
Materials provided by Washington University School Of Medicine. Note: Content may be edited for style and length.
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