Typhoid fever genomes to help scientists seek better vaccines

Every year in developing nations, typhoid fever infects more than 16 million people and kills more than half a million. Researchers hoping to reduce this heavy toll have an important new tool: completed genomes for the two bacteria that are the leading causes of typhoid fever. Scientists at the Genome Sequencing Center (GSC) at Washington University School of Medicine in St. Louis hope the results will hasten the development of new vaccines that can exploit similarities between the strains.

Three years ago, scientists sequenced the genome of the Salmonella bacterium most familiar to Americans because of its role in food poisoning, Salmonella Typhimurium (Salmonella enterica var Typhimurium).

Unlike that bacterium, Typhi and Paratyphi A can spread beyond the gut to cause systemic infections. The bacteria cause problems mainly in developing nations, where they spread through consumption of contaminated food and water.

Salmonella enterica
Salmonella enterica

“Because of our hygiene and the availability of antibiotics, these bacteria aren’t a big problem here. But they are significant sources of mortality in other nations, particularly in children and the elderly,” says Sandra Clifton, Ph.D., research assistant professor in genetics at the GSC. “Learning what the commonalities and the differences are between these two strains will help us seek a vaccine that works against both.”

Clifton was a contributor to the projects that sequenced the genomes of Typhimurium and Paratyphi A. The Paratyphi A project published its results and a Typhi-Paratyphi A comparison in the November 7 issue of Nature Genetics.

The Paratyphi A sequencing project was led by Richard Wilson, Ph.D., director of the GSC and professor of genetics. Other institutions involved were the Sidney Kimmel Cancer Center of San Diego and the University of Calgary.

Typhimurium bacteria can inhabit mice, humans, and other organisms, but Typhi and Paratyphi A have been found only in humans. This exclusivity may make it possible for scientists to eradicate the disease, a feat they accomplished once before with the smallpox virus and hope to repeat soon with polio virus.

Based on their analysis of the Typhi and Paratyphi A genomes, researchers think Typhi, whose genome was sequenced by the Wellcome Trust Sanger Institute, branched off from a bacterial ancestor anywhere from 15,000 to 150,000 years ago.

“That’s a mere second in evolutionary time, and Paratyphi A appears to have developed even later than that,” Clifton notes. “So it’s going to be very interesting to study how these bacteria have rapidly adapted to the human niche.”

Signs that both organisms were evolving on the same but slightly divergent tracks included the number of pseudogenes, or genes still encoded in the bacteria’s DNA but no longer used to make proteins. Both bacteria have similarly large numbers of pseudogenes—Typhi has about 200, and Paratyphi A has approximately 170.

Although similar in quantity, the pseudogenes were different in content.

“We only found about 30 similar pseudogenes between the two genomes,” Clifton notes. “Although the individual genes were different, in many instances the bacteria had turned off different genes involved in the same biochemical processes. That tells us that these bacteria are probably evolving along partly overlapping but very distinct genotypic pathways.”

Clifton and others found the similarities encouraging. They hope further analysis of the genomes will lead to the identification of common genetic elements that can be exploited for creation of vaccines effective against both bacteria.

McClelland M, Sanderson KE, Clifton SW, Latreille P, Porwollik S, Sabo A, Meyer R, Bieri T, Ozersky P, McLellan M, Harkins CR, Wang C, Nguyen C, Berghoff A, Elliott G, Kohlberg S, Strong C, Du F, Carter J, Kremizki C, Layman D, Leonard S, Sun H, Fulton L, Nash W, Miner T, Minx P, Delehaunty K, Fronick C, Magrini V, Warren W, Florea L, Spieth J, Nhan M, Wilson RK. Comparison of genome degradation in Paratyphi A and Typhi, human-restricted serovars of Salmonella enterica causing typhoid. Nature Genetics, November 7, 2004.

Funding from the National Institute of Allergy and Infectious Diseases.