Typhoid occurs across the world, with the highest incidence in Asia and Africa. Surveillance projects are important for determining the geographical burden of the disease and documenting outbreaks. Typhoid is caused by the bacterium Salmonella Typhi, a clonal subspecies composed of a heterogeneous pool of strains. While all S. Typhi are derived from a common ancestor (monophyletic), they have evolved over time as they spread across the globe. This resulted in genetic distinctions between strains from different parts of the world. Such evolutionary changes include mutations of single subunits of DNA (single nucleotide polymorphisms, SNPs), and acquisition or loss of sets of genes (mobile elements). Collecting samples of S. Typhi allows us to compare the strains and determine how they differ from region to region and change over time. We can also construct a family tree (phylogeny) to illustrate how the strains are related to each other and infer transmission events between regions. The advent of whole genome DNA sequencing allows us to interrogate the genetic differences at the highest resolution. Whereas earlier methods looked at variability in a set of just seven genes (multi-locus sequence typing, MLST), we are now able to look at variability across the entire genome and identify DNA fingerprints associated with specific strains. S. Typhi strains with the same DNA fingerprint are said to belong to the same genotype (genetically similar strains).
A Global Collection of S. Typhi
We recently analysed a global collection of 1,832 S. Typhi samples collected from 63 countries over the last century. This data set was collected by a team of collaborators (the International Typhoid Consortium) and sequenced at the Wellcome Trust Sanger Institute. This is the largest collection to date which enabled an unprecedented level of understanding of the S. Typhi phylogeny. We were able to construct a more accurate phylogenetic family tree, create a genotyping scheme to organize the different strains into a tiered framework of relatedness, and document the spread of a dominant multidrug resistant (MDR) strain. You can explore the data from our global collection of S. Typhi or read the original paper, Wong VK et. al., Phylogeographical analysis of the dominant multidrug-resistant H58 clade of Salmonella Typhi identifies inter- and intracontinental transmission events, Nature Genetics, 2015.
Phylogeny and haplotyping (Family tree and classification methodology)
The phylogeny was built to show the relationship between isolates from the collection. The lengths of the branches indicate the number of SNP differences between samples. The phylogeny was bioinformatically divided into groups based on genetic similarity. On the highest level, there are four clusters. The clusters were further divided into sixteen clades and 49 subclades. Regions and countries contain isolates from mixtures of different subclades. Whereas clusters and clades are present in many different regions, many subclades are predominantly linked to single countries or regions. The fact that subclades show region-specificity allows us to roughly correlate genotype to geography. If an isolate is found in an unexpected region based on its genotype, we can assume a transmission event has occurred, perhaps following patient travel. The genotype can be determined to the subclade level based on 68 unique SNPs. Tools developed by researchers at the University of Melbourne and Wellcome Trust Sanger Institute are available to compute the genotype of user input whole genome sequencing data and explore individual isolates in the global collection. Links to these resources can be found here.
H58, a multidrug resistant strain, is spreading globally
The H58 genotype is not limited to a single region: it has been found across Asia, Africa, and Oceania. H58 is of special concern because it is MDR, meaning it is resistant to the first-line treatments of chloramphenicol, ampicillin, and trimethoprim-sulfamethoxazole. You can read more about antibiotic resistance. H58 was first observed in the early 1990s. Based on the phylogeny, there is evidence that South Asia was an early hub. The level of diversity between isolates supports models of historical transmission events from South Asia to Southeast Asia, Pakistan, Fiji, Nepal, and Africa. H58 appears to have been introduced to Africa from South Asia on multiple occasions. Within Africa, H58 is predominantly found in eastern and southern Africa, but not northern, western or central Africa. Looking at the timeline of H58, after it transmits to a new region it becomes the predominant genotype, replacing the previously resident genotype. This suggests that H58 may have an evolutionary advantage over other genotypes. You can explore the geographical distribution of H58 in our global collection of S. Typhi.
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