The molecular epidemiology of Salmonella Typhi and applications for policy
Salmonella Typhi (S. Typhi) is a Gram-negative bacterium and the etiologic agent of typhoid fever. High rates of typhoid were historically associated with urban slums in South Asia with poor sanitation, but recent multicentre surveillance studies have demonstrated that typhoid is also a major problem of urban and rural areas in sub-Saharan Africa. Typhoid necessitates antimicrobial therapy; however, antimicrobial resistance (AMR) poses a serious threat to the effective clinical management of typhoid, particularly in South Asia, where resistance to all oral antimicrobials used to treat typhoid has been reported. New typhoid conjugate vaccines (TCVs) are highly efficacious and two have been prequalified by the World Health Organization (WHO); a small number of countries have introduced TCVs into their national immunization programs. However, many countries lack primary surveillance data to inform decision-making for TCV introduction. Here, aiming to aggregate and analyse globally representative whole genome sequencing (WGS) data to inform public health action, I conducted a genomic investigation of the global distribution and transmission dynamics of AMR S. Typhi. With colleagues from Pakistan and India, I conducted phylogenetic analyses of the first molecularly confirmed azithromycin-resistant S. Typhi isolated in Pakistan and India and put them into context with contemporaneous azithromycin-resistant isolates. I found that single point mutations in acrB (efflux pump) were emerging independently in these settings, potentially associated with selective pressure. AMR in S. Typhi is associated with the H58 lineage, which arose recently before becoming globally dominant within a relatively short time. Given this lineage’s association with AMR, I sought to investigate how, when, and where it emerged. Working with collaborators from the United Kingdom Health Security Agency (UKHSA), we performed phylogenetic and phylodynamic analyses using S. Typhi from returning travellers to the UK between 1980 and 1995. This dataset, which contained the earliest described H58 S. Typhi, indicates that the prototype H58 organisms were MDR, and that they emerged spontaneously in India in 1987 and became radially distributed throughout South Asia. These early organisms were associated with a single long branch and possessed mutations associated with increased bile tolerance, suggesting that the first H58 organism was generated during chronic carriage. The subsequent increased use of fluoroquinolones led to several independent mutations in gyrA, leading to decreased fluoroquinolone susceptibility. The apparent ability of H58 to acquire and maintain AMR genes continues to pose a threat, suggesting that TCVs should be deployed across South Asia to minimise the potential emergence of new drug-resistant variants. I worked with a broad range of collaborators to establish the Global Typhoid Genomics Consortium (GTGC) to encourage sharing of S. Typhi genomic data and standardised metadata, and to enable analysis and visualisation of these data in context to support public health decision-making. Here, I engaged with groups sequencing S. Typhi genomes to analyse and draft a global update paper; the final dataset contained >13,000 sequences. This work provides an updated overview of AMR and genotype distribution and illustrates key international transmission events, with the aim of informing TCV introduction decision-making and treatment guidelines. To create a translational link between laboratory scientists, genomics experts, clinicians, and policy makers, I outlined use cases for WGS in surveillance, diagnostic development, clinical management, and informing vaccine introduction as well as typhoid control. I hope to advance this work by fostering broader participation in the GTGC, and by encouraging funding support for the generation and analysis of S. Typhi WGS data. I also intend to create greater visibility for, and advocate for the value of, such data in conversations with country decision-makers and other policymakers via the WHO.
Antmicrobial resistance, Salmonella Typhi, Typhoid conjugate vaccine, Antimicrobial stewardship, Vaccine introduction, Typhoid genomics
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