Salmonella

We are working collaboratively with researchers globally to analyse the population structure of Salmonella enterica to help identify transmission patterns and support vaccination programmes. This bacterium is the cause of intestinal infections including typhoid and has significant rates of mortality across the world.

By sequencing the genomes of global and local Salmonella bacterial isolates, we are able to build family trees (phylogeny) and stratify populations into definable genetic groups (haplotypes). Our phylogenetic analysis can also be used to study evolutionary trends, antibiotic resistance and virulence. This serves as a framework of genome variation by which we can identify transmission patterns and support vaccination and other control programmes.

[Genome Research Limited]

Background

Salmonella enterica can be differentiated into strains (serovars) that have different disease potential in humans and animals. Most serovars are associated with zoonotic spread from animals in the food chain, such as chickens or cattle, to humans. Zoonotic Salmonella, such as S. Typhimurium and S. Enteritidis, normally cause localized acute gastroenteritis in humans and are often referred to as non-typhoidal salmonella or NTS. NTS infections are common throughout the world, and frequently show virulence in more than one host species.

[Dave Goulding GRL]

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Other S. enterica serovars are host restricted to humans and include S. Typhi and S. Paratyphi A. They cause enteric fever or typhoid, a systemic intestinal infection that can last for several weeks or months if left untreated and can lead to life-threatening gastro-intestinal bleeding or perforation. Typhoid is transmitted through food and water contaminated by the faeces and urine of patients and carriers. Although virtually eradicated in industrialized countries, typhoid fever remains a serious public health problem in the developing world, particularly in parts of Southern Asia, South-East Asia and sub-Saharan Africa. The burden of disease is hard to measure, but according to recent estimates, 22 million cases occur each year in the developing world, causing 216,000 deaths. We have shown through our phylogenetic analysis that typhoid entered the human population approximately 30,000 years ago and all current strains have evolved from this event.

The challenge

Multiple antibiotic resistant strains of S. Typhi and other S. enterica are becoming increasingly common worldwide. New approaches are needed to treat these bacterial infections. Through developing an understanding of the molecular basis of infection and immunity and understanding how disease agents change to evade human intervention such as antibiotics, disinfectants, vaccines, we stand a better chance of developing more effective vaccines and therapies to protect against infections.

However developing this detail picture is complicated by the fact that the Salmonella genus is divided into two species: Salmonella enterica and Salmonella bongori, which are then further divided into six distinct sub-species. Serology is used in classical microbiology laboratories to divide the Salmonella genus into over 2,500 serovars. Whole genome sequencing now offers us the opportunity to accurately type Salmonella serovars with far greater resolution using a more accurate and portable methodology.

Our Research

Sanger Institute scientists and their collaborators around the world have generated a wealth of information on the genome sequences and points of genome variation in different Salmonella including: Bongori, Typhi, Typhimurium, Enteritidis, Gallinarum, Hadar, Infantis, Senftenberg and Paratyphi A. From these analyses, we have identified patterns of evolution that have involved gene acquisition, mediated by mobile genetic elements and Single Nucleotide Polymorphisms (SNPs). Such information can help define the mechanisms of virulence and environmental/host adaptation exploited by Salmonella.

S. Typhi genome

S. Typhi genome [Nature. 2001 Oct 25;413(6858):852-6]

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Through multiple collaborations across the world, we are exploiting genome information and haplotyping to identify transmission patterns and support vaccination-based control programmes for typhoid fever. For S. Typhi we have constructed a high-resolution phylogenetic tree based on shared inheritance of single nucleotide polymorphisms, insertions, deletions and plasmids. All S. Typhi isolates map onto the tree in an unequivocal manner. Clinical, phenotypic and geographic data can also be mapped back to the tree, linking genotype to phenotype. We are currently using this genotype data to map the geographical distribution of S. Typhi within cities such as Kathmandu, Nairobi and Kolkata.

We have extended our phylogenetic analysis to other Salmonella serovars. In collaboration with our International Fellow Sam Kariuki, based in Kenya, we have defined a new form of highly invasive non-typhoidal Salmonella (NTS) disease in the sub-Saharan region associated with high rates of mortality. In other parts of the world NTS are normally associated with diarrhoeal disease across a broad host range but in this region such infections are frequently dramatically more invasive with severe presentation in children and immunocompromised individuals, such as HIV carriers. We have shown through our phylogenetic analysis that a significant proportion of this invasive NTS is due to a novel genotype, ST313, of S. Typhimurium not common outside of this region and its success may be linked to the spread of HIV. ST313 isolates show signs of genome degradation similar to that detected in S. Typhi, suggestion that they may be adapting to the human host.

Partners

Our principle collaborators include:

* quick link - http://q.sanger.ac.uk/94pkmzii