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Sequencing Study Yields Clues to Invasive Salmonella Emergence, Spread in Sub-Saharan Africa

NEW YORK (GenomeWeb News) – The scourge of HIV in sub-Saharan Africa may have created circumstances that helped aid the spread of invasive Salmonella infections in the region, according to a phylogenetic analysis appearing online yesterday in Nature Genetics.

In 2009, an international research group led by investigators at the Wellcome Trust Sanger Institute linked a series of invasive infections in Malawi and Kenya to an antibiotic resistant strain of non-typhoidal Salmonella enterica belonging to the Typhimurium serovar.

That Salmonella Typhimurium strain, called ST313, appeared to show a propensity for infecting individuals with compromised immunity, malnutrition, or other health problems, the researchers noted in their Genome Research study.

Now, members of the same team used whole-genome sequencing and phylogenetics to track the emergence and spread of invasive Salmonella Typhimurium throughout sub-Saharan Africa — an analysis that points to two main Salmonella Typhimurium lineages in the region.

The first of these appears to have emerged roughly 52 years ago in southeastern Africa. That lineage has since been replaced by an invasive and antibiotic resistant Salmonella Typhimurium lineage that began spreading from central Africa nearly two decades later.

Most of the isolates within the newer lineage contain genes that render them resistant to an antibiotic called chloramphenicol, researchers reported, perhaps as a consequence of that drug's use during the prior wave of invasive Salmonella Typhimurium infections.

The timing with which the more recent lineage appeared — and its dispersal patterns also resemble patterns described for HIV — suggest that the bug may have benefited from the compromised immunity that accompanied HIV's spread in the region.

"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 [invasive non-typhoidal Salmonella] wave," Wellcome Trust Sanger Institute Robert Kingsley, co-first author on the new study, said in a statement. "Our findings suggest the current epidemic of iNTS and its transmission across sub-Saharan Africa may have been potentiated by an increase in the critical population of susceptible, immune-compromised people," he added.

The non-typhoid-causing Salmonella enterica serovars found in most parts of the world tend to produce relatively non-invasive infections, often affecting the gastrointestinal tract, Kingsley and co-authors explained. In sub-Saharan Africa, though, a far more invasive and deadly form of non-typhoidal Salmonella disease has appeared.

"The clinical presentation of iNTS disease is distinct from those of both gastroenteritis and typhoid fever," study authors wrote, "and is characterized by a non-specific fever that can be indistinguishable from malaria and in rare cases is accompanied by diarrhea."

Two antibiotic-resistant ST313 Salmonella Typhimurium isolates were sequenced as part of the 2009 Genome Research study. But while the individual genomes provided clues about ST313 biology, they could not be used to discern the invasive Salmonella serovar's history in the region.

To explore this in more detail, researchers used the Illumina GAII to sequence 179 isolates of Salmonella Typhimurium collected around the world over more than 70 years. Of these, 129 were invasive isolates obtained in sub-Saharan Africa between 1988 and 2010, including representatives from Malawi, Kenya, Mozambique, Uganda, the Democratic Republic of the Congo, Nigeria, and Mali.

From these sequences, the team tracked down more than 10,600 SNPs, which were subsequently employed in a phylogenetic analysis of the isolates.

Most of the invasive Salmonella Typhimurium isolates from sub-Saharan Africa fell into one of two STS313 sequence type lineages on a distinct branch of the Salmonella Typhimurium tree.

The first lacked chloramphenicol resistance genes and appears to have arisen in the Malawi area roughly 52 years ago. The other — a primarily antibiotic-resistant group — is thought to have emerged closer to the Congo basin about 35 years ago.

The latter lineage appears to have spread in multiple waves, the researchers reported, largely replacing the more antibiotic-susceptible version of the bug.

"Because it acquired resistance to chloramphenicol, this pathogen has much greater opportunity to survive and spread across the region," senior author Gordon Dougan, head of the Sanger Institute's microbial pathogenesis group, said in a statement.

Given the overlap between invasive Salmonella Typhimurium infection patterns over the past few decades and the timing and geography described for HIV emergence, the team speculated that compromised health and immunity in the sub-Saharan region may have further spurred the spread of the invasive and antibiotic-resistant bacterial pathogens.

"The resulting large pool of immunosuppressed individuals may also facilitate an unusual human-to-human transmission (anthroponotic) component of invasive Salmonella Typhimurium disease, in contrast to most disease caused by [non-typhoidal Salmonella] outside of Africa, where transmission is predominantly zoonotic," researchers explained.

Still, they cautioned that more research is required to understand the types of non-typhoidal Salmonella spread that are possible, where various transmission types occur, and how these events can be avoided.

"There has been some evidence that this disease can be passed from human to human," Dougan said. "Now the race is on to discover how [non-typhoidal Salmonella] is actually transmitted in sub-Saharan Africa so that effective intervention strategies can be implemented."