An extended genotyping framework for Salmonella enterica serovar Typhi, the cause of human typhoid

Abstract

The population of Salmonella enterica serovar Typhi (S. Typhi), the causative agent of typhoid fever, exhibits limited DNA sequence variation, which complicates efforts to rationally discriminate individual isolates. Here we utilize data from whole-genome sequences (WGS) of nearly 2,000 isolates sourced from over 60 countries to generate a robust genotyping scheme that is phylogenetically informative and compatible with a range of assays. These data show that, with the exception of the rapidly disseminating H58 subclade (now designated genotype 4.3.1), the global S. Typhi population is highly structured and includes dozens of subclades that display geographical restriction. The genotyping approach presented here can be used to interrogate local S. Typhi populations and help identify recent introductions of S. Typhi into new or previously endemic locations, providing information on their likely geographical source. This approach can be used to classify clinical isolates and provides a universal framework for further experimental investigations.

Whole Genome Sequence Analysis of Salmonella Typhi Isolated in Thailand before and after the Introduction of a National Immunization Program

“…Typhi from Thailand. An earlier global haplotyping study that included seven Thai isolates [52] identified five distinct haplotypes in Thailand (H3, 1989; H42, 1990; H50, 2002; Vi- H52, 1990; H79, 2002), three of which are related to genotypes that we identified amongst Thai strains in this study (H79, 2.3.4; H52, 3.4; H42, 3.1.2) [32]. Genotype 4.3.1 (H58) was not found amongst our historical Thai isolates.…”

“…It is also possible that the lack of previous reports regarding the diversity of small plasmids in S . Typhi reflects a technological complexity, however, this is bypassed with high-throughput WGS and we detected negligible small plasmid content in the global collection of 1,832 genomes using the same screening approach [4, 32, 58]. Notably, few of the Thai plasmids share nucleotide sequence homology with those previously described in S .…”

“…Typhi isolates collected between 1973 and 1992 were subjected to WGS and SNP analysis. Genome-wide SNPs were used to construct a ML phylogeny and isolates were assigned to previously defined genotypes [32] using a subset of SNPs (see Methods). These analyses subdivided the population into ten distinct genotypes, each corresponding to a specific lineage in the ML phylogeny (Fig 1).…”

“…The resultant allele calls for 68 of these SNPs were used to assign isolates to previously defined lineages according to an extended S . Typhi genotyping framework [32] code available at https://github.com/katholt/genotyphi). SNPs called in phage regions, repetitive sequences (354 kb; ~7.4% of bases in the CT18 reference chromosome, as defined previously [33] or recombinant regions (~180kb; <4% of the CT18 reference chromosome, identified using Gubbins (v1.4.4) [34]) were excluded, resulting in a final set of 1,850 SNPs identified in an alignment length of 4,275,037 bp for the 44 isolates.…”

Salmonella enterica Serovar Typhi Lipopolysaccharide O-Antigen Modification Impact on Serum Resistance and Antibody Recognition

“…Indeed, disease-associated S . Typhi strains are not clonal, and the genetic repertoire of O-antigen-modifying genes may vary (15, 38, 39). Furthermore, the Ty21a oral vaccine elicits a strong O-antigen antibody response (13), and thus, any factors that modify this response may impact serovar and strain cross-reactivity.…”