Evolutionary History of Salmonella Typhi

Abstract

For microbial pathogens, phylogeographic differentiation seems to be relatively common. However, the neutral population structure of Salmonella enterica serovar Typhi reflects the continued existence of ubiquitous haplotypes over millennia. In contrast, clinical use of fluoroquinolones has yielded at least 15 independent gyrA mutations within a decade and stimulated clonal expansion of haplotype H58 in Asia and Africa. Yet, antibiotic-sensitive strains and haplotypes other than H58 still persist despite selection for antibiotic resistance. Neutral evolution in Typhi appears to reflect the asymptomatic carrier state, and adaptive evolution depends on the rapid transmission of phenotypic changes through acute infections.Many bacterial taxa can be subdivided into multiple, discrete clonal groupings (clonal complexes, or ecotypes) that have diverged and differentiated as a result of clonal replacement, selective sweeps, periodic selection, and/or population bottlenecks (1). Geographic isolation and clonal replacement can also result in phylogeographic differences between bacterial pathogens from different parts of the world (2), even within young, genetically monomorphic pathogens (3) (supporting online material text) such as Mycobacterium tuberculosis (4) and Yersinia pestis (5). Typhi is a genetically monomorphic (6), human-restricted bacterial pathogen that causes 21 million cases of typhoid fever and 200,000 deaths per year, predominantly in southern Asia, Africa, and South America (7). Typhi also enters a carrier state in rare individuals [such as Mortimer's example of "Mr. N the milker" (8)], who can shed high levels of these bacteria for decades in the absence of clinical symptoms. Genome sequences are available from strains CT18 (9) and Ty2 (10), but † To whom correspondence should be addressed. E-mail: achtman@mpiib-berlin. Europe PMC Funders Author ManuscriptsEurope PMC Funders Author Manuscripts the global diversity, population genetic structure, and evolutionary history of Typhi were poorly understood. It has been speculated that Typhi evolved in Indonesia, which is the exclusive source of isolates with the z66 flagellar antigen (11).We investigated the evolutionary history and population genetic structure of Typhi by mutation discovery (12) We anticipated that housekeeping genes would exhibit diminished levels of nucleotide diversity, π, as a result of purifying selection, and that pathogenicity genes would exhibit elevated levels as a result of diversifying selection. However, π did not differ significantly with gene category (P > 0.05, analysis of variance) (table S1). Purifying selection should result in Ka/Ks (the ratio of nonsynonymous substitutions per nonsynonymous site to synonymous substitutions per synonymous site) values that are less than 1.0 and diversifying selection should result in ratios higher than 1.0. A trend in this direction was observed (table S1), but it was not particularly strong. We therefore concluded that these 88 BiPs largely reflect the lack of strong selection a...

Insights from genomic comparisons of genetically monomorphic bacterial pathogens

“…The extensive use of antibiotics for treating bacterial diseases of humans and domesticated animals, and as a growth supplement in animal husbandry, has resulted in a very dramatic increase in the frequencies of antibiotic-resistant pathogens. Over a 20 year period, multiple independent mutations that reduce susceptibility to fluoroquinolones have occurred at the same nucleotide(s) in the gyrA gene within all the lineages of serovar Typhi [21]. Similarly, genetic islands encoding resistance to meticillin and other antibiotics have been imported repeatedly in recent decades within one discrete lineage of S. aureus [33].…”

“…Many of the selected variants are apparently less fit than their parents. Despite an increase in the frequency of mutant gyrA alleles in Typhi, each progressive node within the genealogy also included isolates that lacked these mutations [21]. Twenty years of selection by fluoroquinolone treatment have apparently not yet been able to select epistatic mutations that can ameliorate this reduced fitness, and the basal genealogy of Typhi remains susceptible to fluoroquinolones.…”

“…Similar to O157:H7 E. coli, some of these taxa correspond to lineages within a species of greater diversity, e.g. the cause of typhoid fever, serovar Typhi of Salmonella enterica [21] or the cause of pandemic cholera, O1 or O139 Vibrio cholerae [22]. In contrast, other genetically monomorphic lineages have been accorded species status because of the distinctive diseases they cause, e.g.…”

A novel broadly applicable PCR-RFLP method for rapid identification and subtyping of H58 Salmonella Typhi

“…On the contrary, single nucleotide polymorphisms (SNPs) assay has proved to be the most reliable method for S. Typhi genotyping, and over 2000 SNPs were discovered by sequencing different S. Typhi genomes. These SNPs were used to create a phylogenetic tree, which defines 85 S. Typhi haplotypes (H1-H85), originated through the accumulation of genomic mutations from a common ancestor, the haplotype 45 ( Roumagnac et al, 2006, Achtman, 2008and Holt et al, 2008. Moreover, insertions and deletions resulting from recombination events were identified in S. Typhi genomes ( Holt et al 2008).…”

“…The identification of specific SNPs among the H58 population (haplogroup) further defined two principal lineages (I and II) and different sub-lineages (H58A-H58J, H60-H65) ( Holt et al 2008). H58 S. Typhi strains are endemic in Southeast Asia, India and Africa ( Baltazar et al, 2015 andWain et al, 2015), and their wide diffusion has been associated to multidrug-resistance (MDR) to the first-line drugs (ampicillin, chloramphenicol, and trimethoprim-sulfamethoxazole) and to reduced susceptibility to the alternative drugs (fluoroquinolones) used in typhoid fever therapy ( Roumagnac et al, 2006, Achtman, 2008, Holt et al, 2010. The surveillance of H58 S. Typhi is therefore important, especially in areas where typhoid fever is endemic.…”