LONDON ¿ Scrutiny of the genomes of two species of Salmonella bacteria ¿ one the cause of typhoid, the other responsible for a common type of food poisoning ¿ is likely to yield new insights into what makes typhoid a killer. Analysis of hitherto unknown genes also will improve scientists¿ understanding of the origins of bacterial drug resistance, as well as providing many potential targets for drugs to treat Salmonella infections and vaccines to prevent them.

The sequences of the genomes of Salmonella typhi, which causes typhoid, and of Salmonella typhimurium, which is to blame for many episodes of diarrhea and vomiting, have just been published in Nature. That of S. typhi includes some intriguing findings, such as the discovery that part of the DNA of the sequenced isolate has come from Yersinia pestis, the bacterium that causes plague.

Gordon Dougan of Imperial College, London, one of the leaders of the project to sequence S. typhi, which was funded by the UK-based Wellcome Trust, said: ¿The genetic blueprint of Salmonella is already leading to new methods of treatment and control, and better diagnostic tests.¿ These include tests that are being used in hospitals in Vietnam that allow clinicians to detect multidrug-resistant strains of S. typhi, and which may eventually provide rapid diagnosis of typhoid in patients presenting with fever.

Dougan is one of 41 scientists who took part in the S. typhi project. As well as colleagues at Imperial College, other collaborators were based at the Wellcome Trust Sanger Institute in Cambridge, UK; the University of Oxford-Wellcome Trust Clinical Research Unit in Ho Chi Minh City, Vietnam; the Centre for Tropical Diseases, also in Ho Chi Minh City; and the Technical University of Denmark in Lyngby, Denmark. Their paper is titled: ¿Complete genome sequence of a multiple drug-resistant Salmonella enterica serovar Typhi CT18.¿

The group that sequenced S. typhimurium was led by Richard Wilson, associate professor of genetics and co-director of the Genome Sequencing Center at Washington University School of Medicine in St Louis, and included investigators at the Sidney Kimmel Cancer Center in San Diego, the University of Calgary in Alberta, Canada, and Pennsylvania State University at University Park. The title of their paper is: ¿Complete genome sequence of Salmonella enterica serovar Typhimurium LT2.¿

Salmonella enterica serovar Typhi, otherwise known as ¿Typhi,¿ is notorious for infecting about 17 million people worldwide every year with typhoid fever, and killing about 600,000 of them. It is transmitted when people consume contaminated food or drink. Isolates of S. typhi are all very closely related. That sequence, called CT18, was isolated from a 9-year-old boy in December 1993 in the Mekong Delta region of Vietnam. It is resistant to all cheap antibiotics and there is a risk that it soon will become untreatable.

Jeremy Farrar, of the University of Oxford-Wellcome Trust Clinical Research Unit in Vietnam, said: ¿There is a real threat of untreatable typhoid emerging in the next few years in some countries. Already, 90 percent of strains in Vietnam are reported to be resistant to most available drugs, even those which have only just been developed.¿ He added that he hoped the collaborative sequencing project would lead to a vaccine that all countries would be able to afford.

Dougan said comparison of the strain sequenced with other strains that are not drug resistant would allow researchers to analyze which genes are involved in conferring drug resistance. He told BioWorld International: ¿We can now look at how drug resistance evolved and make predictions about how it might evolve further.¿

The sequence shows that Typhi has 4,600 genes, as well as 200 more on one plasmid and 100 more on another. Dougan added: ¿We discovered five new islands of pathogenicity¿ ¿ genes which we think are dedicated to pathogenicity, and which are not present in other organisms.¿

Typhi also has many ¿pseudogenes¿ ¿ coding sequences that resemble genes but do not seem to have any function. These are genes that probably were needed to invade other hosts but which have become redundant as the bacterium has become more closely adapted to its human host.

Dougan said: ¿We now know that typhoid emerged only once in human history, at some time in the last 20,000 years, most likely during early settlements. Because there is no animal reservoir for typhoid, if we can eliminate it from humans it would likely eradicate the disease altogether as typhoid could not emerge from other Salmonella easily.¿

Salmonella enterica serovar Typhimurium, otherwise known as ¿Typhimurium,¿ was sequenced by the North American group, and infects humans, cattle, chickens and other warm-blooded animals. It is thought to cause around 1.4 million cases of food poisoning in the U.S. each year, with about 1,000 deaths.

Wilson said antibiotic resistance is an increasing problem in Typhimurium infections. ¿We hope this work will identify possible new drug targets and reduce the threat of ever-more resistant strains of the bacterium,¿ he added.

The researchers identified 4,595 suspected genes in the Typhimurium genome, many of which were previously unknown. They include 156 genes that probably code for membrane proteins that are potential drug or vaccine targets. The study also pinpointed two gene clusters that contain the information for making the fimbriae ¿ the hair-like strands that cover the bacteria. These enable the bacterium to cling to cells that line the intestinal tract.

Sandra Clifton, group leader for the project, based at the Department of Genetics at Washington University, said: ¿These [fimbriae] are also targets for potential therapies that might prevent the bacterium from attaching in the gut and thereby preclude infection.¿

Comparison of the genome of Typhimurium with those of several closely related bacteria revealed that Typhimurium has many genes ¿ many of them previously unknown ¿ that are missing from subspecies of Salmonella that infect cold-blooded animals. Clifton added: ¿Those genes may enable Typhimurium to infect warm-blooded hosts.¿

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