Hope for tackling deadly bacterial disease

Ubon, a city in Northeast Thailand, has the unenviable title of being the world’s capital of melioidosis. Caused by infection with Burkholderia pseudomallei bacterium, it is estimated that 165,000 people a year around the world develop the disease, and more than half of those die from the infection. The numbers are stark, and likely to be a huge underestimate, as diagnosing the diseases isn’t always possible.

Despite the high mortality rate, and the fact that prevention and antibiotic treatment are both possible, the condition is not well studied. It doesn’t even make it onto lists of neglected tropical diseases.

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, an International Fellow at the Wellcome Sanger Institute. “Ubon is the capital because we’re looking for the disease. If you don’t look, you won’t find it,” says Claire.

Claire is on a mission to change things in Ubon and beyond. She’s built global collaborations to study the disease and the bacterium that causes it.

A key element is her work to understand the genetics of Burkholderia pseudomallei, as well as human genetic factors that might explain why some people infected become ill when others don’t. Her team is also investigating its epidemiology and evolution. She is involved in public health initiatives to raise awareness of the condition and prevent infection. Her most recent work has been to develop a rapid diagnostic test for the disease. The test could potentially save lives from melioidosis.

An advocate for those affected by melioidosis, she is determined to improve outcomes for patients. “Collaboration has so much power,” says Claire. “And patience is key. It fosters creativity. I think we have to be more innovative in the way that we do science in resource-limited places. But when it works here, we can be confident it is going to work anywhere in the world.”

Burkholderia pseudomallei in the laboratory. Credit: Claire Chewapreecha

The burden of melioidosis

The Burkholderia pseudomallei bacterium lives in the environment, in soil and water. In Southeast Asia, many of those infected 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, though it is not yet clear why. Diagnosis is difficult, as symptoms of the infection mimic those of many other diseases. To confirm melioidosis, the current gold standard test is a bacterial culture, where bacteria are isolated from blood, sputum or urine of suspected cases. Results can take several days to come back, by which time it’s often too late and the patient has died from the infection.

The new test that Claire and her team have developed is based on CRISPR technology¹, and detects bacterial DNA in a sample. It doesn’t need specialist equipment, is specific, and is more accurate than the culture test. It reduces diagnosis times from days to hours. The hope is that clinicians can use it to quickly test for the disease, and then treat the condition with the right antibiotics. She is now planning a clinical trial together with colleagues at Ubon hospital, to prove the test saves lives, and that it is cost effective.

“Working in rural Thailand has many limitations. But we have shown that limitations breed innovation, and what succeeds here can succeed anywhere. I am so proud of the team behind this new, robust rapid diagnostic test for melioidosis, and hope that it can be used anywhere in the world to get the right treatments to patients faster, ultimately saving lives."

Dr Claire Chewapreecha,
Sanger Institute International Fellow

Bacterial genetics

Alongside the diagnostic test, Claire is currently working with Professor Nick Thompson at the Sanger Institute, 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 – the bacteria regularly ‘swap’ their DNA. This process helps the bacterium survive in different geographical locations, and results in a diverse population². 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 the bug³.

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

Claire is working to assess this risk, and determine if any bacterial variants could escape the vaccine in development. She is also studying the bacterium’s evolution in terms of antibiotic resistance, something that is fortunately limited so far.⁵

Credits: Claire Chewapreecha.

Host factors

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 Wellcome⁸, and working together with Dr Emma Davenport at the Sanger Institute, 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 not only the most harmful bacteria, but also the most susceptible people, and allow them to protect individuals at high risk of melioidosis infection⁹.

“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."

Dr Claire Chewapreecha,
Sanger Institute International Fellow

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 her 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.