Improving treatment outcomes in tuberculous (TB) meningitis.
Tuberculosis (TB) is a very common infectious cause of death worldwide. Although usually thought of as a lung disease, the bacteria that cause TB can also cause meningitis (TBM). This is the most severe form of TB, killing 20 - 40% of people affected, including in the UK, with children, HIV-infected people and recent immigrants at particular risk. TBM is currently treated with a combination of anti-inflammatory and antibiotic drugs, but the best drugs and drug combinations are not well understood.
It is vital to investigate how TB causing bacteria enter the brain, and how the brain responds to infection and treatment. This will help increase understanding of why some people have poorer outcomes compared with others who receive the same treatment, and potentially guide the development of new drugs.
What the research team will do
A clinical trial for TBM treatment (LASER TBM), funded by Wellcome and others, is currently underway in South Africa.
This UK research team has a unique opportunity to use samples of blood and cerebrospinal fluid (CSF), together with detailed clinical information on the outcomes of treatment, from 100 patients taking part in this trial. By analysing these samples, the researchers will investigate whether there are certain molecules in the blood or CSF that indicate a poor outcome and if these molecules can be changed with better treatment.
At the same time, the team will develop a model using different cell types from the brain and use it to study how these cells interact with the bacteria that cause TB. The model will also be used to test the effects of new antibiotics and anti-inflammatory drugs, both alone and in combination.
How this research will help fight meningitis
This research will increase understanding of TBM and how the drugs currently used to treat it work in the body. It could also lead to the development of new drugs or drug combinations. Although this study is in people who have TB meningitis, the results could also be relevant to other types of meningitis.
Progress so far
Over the past 12 months, the COVID-19 pandemic has continued to affect the progress of this project. Due to this, the research team has been granted a no-cost extension to December 2023 to allow completion of the study.
Despite the delays, progress has been made in the following areas:
Analysis of samples from patients (54) recruited into the original trial is continuing, both at the Francis Crick Institute and also in the USA (once export permits are available).
Recruitment of patients into the larger trial is ongoing; additional study sites have opened which will further increase the chance of recruitment. The necessary agreements are in place for transport of samples to the Francis Crick Institute.
Work on the interactions of BBB and Mycobacterium tuberculosis continued to be disrupted due to COVID-19, but as a result of the pandemic, a new aim has been added to this study to investigate the effects of coronavirus SARS-CoV-2 on the BBB. Results demonstrate that this virus affects the BBB and cells in the central nervous system, and could contribute to the neurological disorders described in patients who have been infected during the pandemic.
Additional staff (not salaried by the Meningitis Now grant) have been recruited to the study team. This will further enhance the outcomes of the project.
In the next 6 months, further samples will be collected from patients enrolled in the larger trial and analysed. Work on the interactions of BBB and Mycobacterium tuberculosis will recommence, and results from the study investigating the effects of SARS-CoV-2 on the BBB will be prepared for publication.
This has been a very challenging first year. Due to delays associated with the COVID-19 pandemic, resulting in the closure of clinical sites for patient recruitment in South Africa, only 52 out of the 100 anticipated patients were recruited through the original study. However, a larger study has started that will allow recruitment of additional patients for our planned experiments. During disruption caused by lockdowns, the team also established a study to investigate neurological manifestations of COVID-19 that will be reported shortly.
Achievements during the past 12 months include collection and processing of samples from 45 patients in South Africa that were processed further at the Francis Crick Institute. However, results are currently pending due to suspension of all non-COVID-related work.
Further achievement was the development of the in vitro blood-brain-barrier (BBB) model to study the interaction between human cells from the central nervous system and Mycobacterium tuberculosis. Firstly, the behaviour of individual cell types was investigated, followed by the complete system put together. However, this whole system could only be studied in small numbers due to delays associated with the pandemic.
In the next 6 months, the research team anticipate processing further samples at the laboratory in South Africa, followed by their shipment to the Francis Crick Institute for analysis, as well to the USA for additional analysis. It is also hoped that the findings in the BBB model system can be confirmed in larger numbers.