A forgotten disease

Dr Claire Chewapreecha recently joined the Sanger Institute as an International Fellow. We spoke about her work on melioidosis, a neglected, often fatal, bacterial disease present in equatorial regions of the world. 

Mun River, Northeastern Thailand. Credit: Claire Chewapreecha

By Alison Cranage, Science Writer at the Wellcome Sanger Institute.

Ubon, a city in Northeast Thailand, has the unenviable title of being the world’s capital of melioidosis. Caused by a bacterial infection, it’s estimated that 165,000 people a year around the world develop the disease, and more than half of those affected die from it. The numbers are likely to be a huge underestimate, as testing for the presence of the bacteria isn’t always possible. Despite the high mortality rate, and the fact that prevention and treatment are possible, the condition is not well studied, and does not make it onto lists of neglected tropical diseases. However, the bacterium does make it on to the Centers for Disease Control and Prevention ‘Tier 1 select agent’ list as a potential bioweapon1.  

Dr Claire Chewapreecha began studying melioidosis after visiting a hospital in Ubon and seeing patients affected. She is a computational biologist based at the Mahidol Oxford Tropical Medicine Research Unit in Bangkok, Thailand, and an International Fellow at the Wellcome Sanger Institute. She works to understand the genetics of the Burkholderia pseudomallei bacterium that causes the disease. She is also investigating why some people infected become ill and others don’t. In collaboration with researchers around the world, she is involved in vaccine trials for the disease and public health initiatives to raise awareness of the condition.

The burden of melioidosis

We started by discussing the impacts of melioidosis around the world. The bacterium responsible for the disease, Burkholderia pseudomallei, lives in the environment, in soil and water. In Southeast Asia, many people who catch it are farmers working in rice paddy fields. The bacterium can enter the skin through a cut or graze, though it might also be caught by consuming contaminated food or water, or by inhalation. People with diabetes are at a much greater risk of melioidosis. Diagnosis is difficult, as symptoms of the infection mimic those of many other diseases. To confirm melioidosis, a bacterial culture test, where bacteria are isolated from blood, sputum or urine of suspected cases is still employed. Results can take several days to come back, by which time, the patient has often died from the infection.

“Timely diagnosis and a vaccine are key clinical interventions that could save many lives from melioidosis. Both are still under development. While we wait for that research to be done, people are working on public health interventions – promoting protective clothing for farmers, for example,” says Claire.

Images show sessions that trialed protective gear and calendars with individual photographs and self-pledges as a reminder tool to boil water and wear boots. From Suntornsut P, et al. Feasibility and initial outcomes of a multifaceted prevention programme of melioidosis in diabetic patients in Ubon Ratchathani, northeast Thailand. PLoS Negl Trop Dis 12(9): e0006765.

“Thai people love to take selfies, so that’s been incorporated into public health campaigns.”2

Bacterial genetics

Claire’s current work in collaboration with the Sanger Institute is focusing on the genetics of Burkholderia pseudomallei. She is seeking to uncover what makes it so virulent, as well as so variable in its effects. It is a species with high levels of genetic recombination – which means that the bacteria regularly ‘swap’ their DNA. This process facilitates bacterial survival across different geographical locations, and results in a diverse population3.  Claire uses genome-wide association studies (GWAS) to compare the genomes of Burkholderia pseudomallei in the environment to those from infected patients. The team has been able to identify genes associated with different properties of these bacteria4.  

“We found genetic variations associated with disease-causing isolates in a gene that codes for hemolysin-coregulated protein (Hcp)4. The protein is both a substrate and a component of Type VI Secretion System –  a ‘needle’ that the bacterium uses to puncture and enter human cells. Reassuringly, Hcp is already part of the conjugate vaccine that is currently in trial, as well as the target for a rapid diagnostic test5,6.  It’s good to see our findings match up. However, it is possible that a genetic change at this location would create both vaccine and rapid test escape bacteria at the same time”

To predict the vaccine lifespan, Claire is working to assess if any bacterial variants could escape the vaccine. She is also investigating selection pressures on the bacterium.

Using genome-wide epistasis and co-selection studies (GWES), the team identified the mutation pairs in genes that are passed on to bacterial descendants together – termed co-selection. They found that genes active during physical stress, particularly those essential for bacterial survival under nutrient depletion, were co-selected7. Claire reasoned that if the co-selected genes are co-regulated under physical stresses, then these conditions should reflect the selective pressures the bacteria faces.

Claire explains: “Soil sampling studies have shown that the bacteria are commonly found in nutrient depleted soil. Agricultural practice that induces loss of soil nutrients, such as crop rotations with short-term fallows and post-harvest residue burning, is not uncommon in melioidosis endemic areas. This has been linked to soil nutrient depletion and may contribute to the prevalence of B. pseudomallei.”

Claire’s work into the bacterial genomes does not fully explain the difference in melioidosis outcomes and severity for people, and so she is investigating human host and environmental factors too, aiming to build a complete picture.

Funded by Wellcome7, her team has been collecting and sequencing the genomes of bacterial and host samples in Ubon. These span patient acute blood samples, bacteria isolated from patients, and the bacterial population collected from patient’s household water supply. Claire hopes that this collection will enable her team to identify biomarkers for the most harmful bacteria and susceptible populations, and allow them to protect individuals at high risk of melioidosis infection.

Recognition

Despite the global burden of melioidosis, the disease is not well recognized. The impacts of the condition are likely to worsen as rates of diabetes, which is a major risk for melioidosis, increase in low- and middle-income countries. Climate change may also affect the disease, as cases have clustered with severe weather events.

Claire is working closely with Thai public health authorities and policy makers to communicate their findings, and working out the best way to communicate results to the public. She is also part of a global community of researchers working on the disease, and hopes that resources for research, from both local and international sources, will expand.

“There is an urgent need for better diagnoses, treatments and resources to tackle melioidosis. I am very keen to raise awareness of this super neglected disease.” 

Claire Chewapreecha

Find out more

References

  1. https://www.cdc.gov/selectagent/faq-general.html
  2. https://journals.plos.org/plosntds/article?id=10.1371/journal.pntd.0006765
  3. https://www.nature.com/articles/nmicrobiol2016263
  4. https://www.nature.com/articles/s42003-019-0678-x
  5. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5736816/
  6. https://journals.asm.org/doi/10.1128/jcm.00346-18?permanently=true&
  7. https://www.biorxiv.org/content/10.1101/2020.08.11.245894v3.full
  8. https://wellcome.org/grant-funding/people-and-projects/grants-awarded/dissecting-genetic-basis-melioidosis-infection