Researchers at the University of Liverpool say they have relied on the combined power of genomics and epidemiology to understand how a type of Salmonella bacteria evolved to kill hundreds of thousands of immunocompromised people in Africa.

Bloodstream infections caused by a drug-resistant type of Salmonella Typhimurium called ST313 are a major public health concern in Africa, where the disease is endemic. What was missing was an understanding of the timing of the major evolutionary events that equipped African Salmonella to cause bloodstream infections in humans.

In a new paper (“Stepwise evolution of Salmonella Typhimurium ST313 causing bloodstream infection in Africa”) published in Nature Microbiology, a team of scientists from the U.K., France, and Malawi, sampled two collections of Salmonella isolates from African patients with bloodstream infections, spanning 1966 to 2018, to piece together the evolutionary journey of the Salmonella over 50 years of human infections in Africa, including the discovery of a new lineage of antibiotic-susceptible ST313.

“Bloodstream infections caused by nontyphoidal Salmonella are a major public health concern in Africa, causing ~49,600 deaths every year. The most common Salmonella enterica pathovariant associated with invasive nontyphoidal Salmonella disease is Salmonella Typhimurium sequence type (ST)313. It has been proposed that antimicrobial resistance and genome degradation has contributed to the success of ST313 lineages in Africa, but the evolutionary trajectory of such changes was unclear,” the researchers wrote.

“Here, to define the evolutionary dynamics of ST313, we sub-sampled from two comprehensive collections of Salmonella isolates from African patients with bloodstream infections, spanning 1966–2018. The resulting 680 genome sequences led to the discovery of a pan-susceptible ST313 lineage (ST313 L3), which emerged in Malawi in 2016 and is closely related to ST313 variants that cause gastrointestinal disease in the United Kingdom and Brazil.

“Genomic analysis revealed degradation events in important virulence genes in ST313 L3, which had not occurred in other ST313 lineages. Despite arising only recently in the clinic, ST313 L3 is a phylogenetic intermediate between ST313 L1 and L2, with a characteristic accessory genome.

“Our in-depth genotypic and phenotypic characterization identifies the crucial loss-of-function genetic events that occurred during the stepwise evolution of invasive S. Typhimurium across Africa.”

The study was led by Jay Hinton, PhD, professor of microbial pathogenesisat the University of Liverpool, who has been researching Salmonella for more than 30 years and leads the 10,000 Salmonella Genomes Project, a worldwide effort to understand the epidemiology, transmission, and virulence of invasive non-typhoidal Salmonellosis.

“Through a remarkable team effort we have removed some of the mystery about the evolution of African Salmonella,” said Hinton. “We hope that by learning how these pathogens became able to infect the human bloodstream we will be better prepared to tackle future bacterial epidemics.”

In the study, scientists sequenced the genomes of 680 Salmonella isolates, from archives kept by the Malawi Liverpool Wellcome Trust (MLW) clinical research program and the Institute Pasteur, and used them to uncover the timeline of crucial genetic events responsible for the infection of immunocompromised humans by S. Typhimurium ST313.

Mutations that influenced gene function during the evolution of ST313 were identified for the first time.

The team also discovered a new antibiotic-susceptible lineage of ST313 that emerged in Malawi in 2016 and is closely related to Salmonella variants that cause stomach infections in the United Kingdom and Brazil. The researchers speculate that changes in antibiotic usage in Malawi between 2002 and 2015 could have created a window of opportunity for the emergence of this new antibiotic-susceptible ST313 lineage.

“By combining the power of genomic analysis with epidemiology, clinical observations, and functional insights, we have shown the value of using an integrated approach to link scientific research with public health,” noted Caisey Pulford, PhD, who carried out much of the research as part of her PhD.

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