The origins of haplotype 58 (H58) Salmonella enterica serovar Typhi

Abstract

Antimicrobial resistance (AMR) poses a serious threat to the clinical management of typhoid fever. AMR in Salmonella Typhi (S. Typhi) is associated with the H58 lineage, which arose comparatively recently before becoming globally disseminated. To better understand when and how this lineage emerged and became dominant, we performed detailed phylogenetic and phylodynamic analyses on contemporary genome sequences from S. Typhi isolated in the period spanning the emergence. Our dataset, which contains the earliest described H58 S. Typhi, indicates that the prototype H58 organisms were multi-drug resistant (MDR). These organisms emerged spontaneously in India in 1987 and became radially distributed throughout South Asia and then globally in the ensuing years. These early organisms were associated with a single long branch, possessing mutations associated with increased bile tolerance, suggesting that the first H58 organism was generated during chronic carriage. The subsequent use of fluoroquinolones led to several independent mutations in gyrA. The ability of H58 to acquire and maintain AMR genes continues to pose a threat, as extensively drug-resistant (XDR; MDR plus resistance to ciprofloxacin and third generation cephalosporins) variants, have emerged recently in this lineage. Understanding where and how H58 S. Typhi originated and became successful is key to understand how AMR drives successful lineages of bacterial pathogens. Additionally, these data can inform optimal targeting of typhoid conjugate vaccines (TCVs) for reducing the potential for emergence and the impact of new drug-resistant variants. Emphasis should also be placed upon the prospective identification and treatment of chronic carriers to prevent the emergence of new drug resistant variants with the ability to spread efficiently.

Global diversity and antimicrobial resistance of typhoid fever pathogens: insights from 13,000SalmonellaTyphi genomes

“…Southern Asia was the most represented region, with 6,623 genomes suitable for prevalence analysis. The genotype distribution confirms the widely-reported finding that the H58 lineage (4.3.1 and derived genotypes) is the dominant form of Typhi in Southern Asia, where it is thought to have originated (Carey et al, 2022;Roumagnac et al, 2006;da Silva et al, 2022;Wirth, 2015;Wong et al, 2015) [n=736/1,275], respectively), which was rare in Bangladesh (0.6%; n=9/1,591) and Pakistan (3.2%; n=47/1,484). In India, H58 lineage 1 (4.3.1.1) was also present at appreciable frequency (12%; n=268/2,267) as was 4.3.1 (i.e.…”

“…This plasmid accumulated genes (bla TEM-1 , cat, dfr and sul) encoding resistance to all three first-line drugs, mobilised by nested transposons (Tn6029 in Tn21, in Tn9) (Holt et al, 2011b;Wong et al, 2015). The earliest known H58 isolates were MDR, and it has been proposed that selection for multidrug resistance drove the emergence and dissemination of H58 (Holt et al, 2011b), which is estimated to have originated in South Asia in the mid-1980s (Carey et al, 2022;da Silva et al, 2022;Wong et al, 2015) before spreading throughout South East Asia (Holt et al, 2011a;Thanh et al, 2016b) and into Eastern and Southern Africa (Feasey et al, 2015;Kariuki et al, 2010;Wong et al, 2015). The MDR transposon has subsequently migrated to the Typhi chromosome on several independent occasions (Ashton et al, 2015;Wong et al, 2015), allowing for loss of the plasmid and fixation of the MDR phenotype in various lineages.…”

RpoS activates formation ofSalmonellaTyphi biofilms and drives persistence in the gall bladder

“…Finally, a strong correlation has been observed between the ability to form biofilms and the duration of STy shedding and carriage in typhoid patients from Pakistan [83] . Most recent phylogenomic analysis has proposed that the ancestral H58 haplotype originated in a chronic carrier from India and evolved to give rise to the three sub-lineages that cause a majority of typhoid infections in Asia and Africa [23] . In the light Strains deleted of iraP, rpoS, waaZ, sthC or tviD and the wild type H58 strain were grown for 12 hours in Luria-Bertani broth at 37C/250 rpm and the absorbance at 600 nm was measured every 2 hours.…”

Global diversity and antimicrobial resistance of typhoid fever pathogens: Insights from a meta-analysis of 13,000 Salmonella Typhi genomes

“…This plasmid accumulated genes ( bla TEM-1 , cat , dfr, and sul ) encoding resistance to all three first-line drugs, mobilised by nested transposons (Tn 6029 in Tn 21 , in Tn 9 ) ( Holt et al, 2011b ; Wong et al, 2015 ). The earliest known H58 isolates were MDR, and it has been proposed that selection for MDR drove the emergence and dissemination of H58 ( Holt et al, 2011b ), which is estimated to have originated in South Asia in the mid-1980s ( Carey et al, 2022 ; da Silva et al, 2022 ; Wong et al, 2015 ) before spreading throughout South East Asia ( Holt et al, 2011a ; Pham Thanh et al, 2016b ) and into Eastern and Southern Africa ( Feasey et al, 2015 ; Kariuki et al, 2010 ; Wong et al, 2015 ). The MDR transposon has subsequently migrated to the Typhi chromosome on several independent occasions ( Ashton et al, 2015 ; Wong et al, 2015 ), allowing for loss of the plasmid and fixation of the MDR phenotype in various lineages.…”