12:11am Thursday 17 August 2017

Whole-genome sequencing tracks spread of severe intestinal disease in sub-Saharan Africa

The pool of people with compromised immune systems caused by HIV infection may have provided a reservoir for the Salmonella bacteria to evolve to become better at infecting humans, suggest the researchers.

People usually become infected with Salmonella bacteria after eating contaminated meat, which leads to an acute bout of food poisoning that normally resolves itself within a few days. Less than one case in every 100 is fatal. In sub-Saharan Africa, however, Salmonella bacteria are a frequent cause of invasive bacterial disease that kills approximately one in four people who catch it. The disease, known as invasive non-typhoidal Salmonella (iNTS), causes a diverse range of symptoms, including fever and respiratory problems.

A recent review of studies on iNTS highlighted malnutrition and co-infection with malaria or HIV as important risk factors for developing the disease, which might explain why the infection is more severe in sub-Saharan Africa than in the rest of the world.

To investigate this, researchers at the Wellcome Trust Sanger Institute sequenced the DNA of clinical samples of bacteria taken from patients with iNTS in Malawi, Kenya, Mozambique, Uganda, the Democratic Republic of the Congo, Nigeria and Mali. They found that the disease is caused by a new strain of the Salmonella bacteria that is rarely isolated from outside of sub-Saharan Africa.

By dating when each sample first emerged and overlaying this with geographical information, the team created a ‘family tree’ showing how the new strain of bacteria had evolved over time. They found that this invasive disease emerged through two very closely related waves of infection. The first wave originated from a possible south-eastern hub about 52 years ago and the second originated about 35 years ago, possibly from the Congo Basin, apparently mirroring the spread of HIV.

Dr Robert Kingsley, joint first author from the Wellcome Trust Sanger Institute, said: “The HIV epidemic in sub-Saharan Africa is thought to have begun in a central region and underwent expansion eastwards, a strikingly similar dynamic to that observed for the second iNTS wave.”

The genome sequencing also revealed that the bacteria appear to be evolving to become more typhoid-like, making them more able to spread efficiently around the human body after infection.

Professor Rob Heyderman from the Malawi-Liverpool-Wellcome Trust Clinical Research Programme, who provided some of the clinical samples from a local epidemic of iNTS that has been carefully characterised, said: “Our findings seem to suggest that people with compromised immune systems caused by HIV, malaria and malnutrition have provided a population in sub-Saharan Africa that is large enough for this devastating bacteria to infect, adapt and circulate.”

The team identified that the vast majority of samples from the second wave of iNTS contain a gene that makes them resistant to chloramphenicol, a frontline antibiotic in the treatment of Salmonella. This gene was not present in the samples from the first wave of iNTS, suggesting that iNTS acquired antibiotic resistance early on in the evolution of the second wave, probably around the time of its spread from the Congo Basin. Acquiring antibiotic resistance so early will have given the bacteria much greater opportunity to survive and spread across the region.

Professor Gordon Dougan, lead author from the Wellcome Trust Sanger Institute, said: “This is the first time that the power of whole-genome sequencing has been used to track the spread of iNTS. Our research highlights the power this approach has to monitor the emergence and spread of dangerous pathogens both locally and globally over time.

“There has been some evidence that this disease can be passed from human to human. Now the race is on to discover how NTS is actually transmitted in sub-Saharan Africa so that effective intervention strategies can be implemented.”

The study was funded by the Wellcome Trust and a Clinical Research Fellowship from GlaxoSmithKline.

Image: Salmonella typhimurium (red) invading cultured human cells. Credit: Microbe World on Flickr

References

Okoro CK et al. Intra-continental spread of human invasive Salmonella typhimurium pathovariants in sub-Saharan Africa. Nat Genet 2012 30 September [epub].

Feasey NA et al. Invasive non-typhoidal salmonella disease: an emerging and neglected tropical disease in Africa. Lancet 2012;379:2489-99.

Wellcome Trust, Gibbs Building, 215 Euston Road, London NW1 2BE, UK T:+44 (0)20 7611 8888

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