A genomic survey of typhoid fever in Zimbabwe has shown how the bacteria behind recent outbreaks evolved extra levels of antimicrobial resistance.
Researchers from the National Microbiology Reference Laboratory, Quadram Institute and University of East Anglia were part of the locally led effort to trace the spread of resistance genes, which is now supporting management of the disease.
The COVID-19 pandemic highlighted how genome sequencing can be used to track the evolution of -disease-causing microbes. By reading the genetic sequence of thousands of virus samples, scientists could track the smallest changes in the genetic code and link these to different variants’ abilities to cause infection or evade vaccines.
Now, in a study published in The Lancet Microbe journal, genome sequencing has been used to study another deadly disease, typhoid fever, and how it’s starting to overcome our defences against it.
Typhoid fever claims over 135,000 lives annually, and with up to 18 million infections it presents a significant burden on healthcare, especially in low-resource countries in South Asia and Africa. It’s caused by Salmonella enterica serotype Typhi (S. Typhi) bacteria that live in humans, infecting the gut and spreading to the liver, spleen and gall bladder. Typhoid is highly infectious, most often transmitted through contaminated food and water.
Treating typhoid relies on antimicrobials but in the last couple of decades, antimicrobial resistance (AMR) has made controlling it much harder. This has been seen in Zimbabwe, where since 2009 there have been multiple typhoid outbreaks, caused by resistant S. Typhi strains. In response, an emergency reactive vaccination campaign using Typhoid Conjugate Vaccine (TCV) was initiated in suburbs of Harare in 2019, providing moderate protection.
To get a picture of the strains of S. Typhi responsible, and how they evolved antimicrobial resistance, researchers from the NMRL in Harare and University of Pretoria, along with an international consortium, including the Quadram Institute and the World Health Organization, turned to genomic sequencing. The researchers were funded by the Bill & Melinda Gates Foundation and the Biotechnology and Biological Sciences Research Council, part of UKRI.
Working with local health authorities in Harare, they sequenced the genomes of 85 S. Typhi samples obtained from people with confirmed typhoid fever from 2012 to 2019, plus an extra 10 from clinical infections in the UK that were associated with travel to Zimbabwe.
From this they could construct a “family tree” showing how the strains were related and evolved over time.
Most of the strains sequenced came from a subbranch of a globally distributed multi-drug resistant S. Typhi, known as 4.3.1.1. Their genomic detective work linked these to a common ancestor first seen in Zimbabwe in 2009, coinciding with renewed typhoid outbreaks. This transmission looks to have derived from S. Typhi previously tracked from Southern Asia into Kenya and Tanzania and subsequent spread south into Malawi.
Of concern is that since 2009, S. Typhi in Zimbabwe has become even more resistant to antimicrobials. Within three years nearly two thirds of isolates studied had gained extra genes including those conferring additional resistance to antibiotics.
The insidious increase in resistance is a major concern, but this study does start to give a handle on the current state of the problem. Diagnostic tests to identify which resistance genes are present can help decide on the most effective treatment and help in the clinical management of typhoid fever in Zimbabwe.
The genomic analysis contributed to the decision to initiate a mass typhoid vaccination campaign in Harare, Zimbabwe. This study will be valuable in assessing the effectiveness of the campaign by providing a baseline view of the S. Typhi population beforehand. Ongoing genomic surveillance could also identify any “escape mutants” allowing healthcare authorities in Zimbabwe to react swiftly and help control typhoid fever and its devastating effects on morbidity and mortality.
ReferenceS:
Population structure of Salmonella enterica Typhi in Harare, Zimbabwe (2012-2019) before typhoid conjugate vaccine rollout: a genomic epidemiology study, Gaetan Thilliez, Tapfumanei Mashe et al The Lancet Microbe DOI: 10.1016/S2666-5247(23)00214-8 is published at https://www.thelancet.com/journals/lanmic/article/PIIS2666-5247(23)00214-8/fulltext
