Improving treatment outcomes in tuberculous (TB) meningitis.
Background
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.
Summary and Impact of research
The research team have investigated samples of blood and cerebrospinal fluid from patients with TB meningitis (TBM). Analysis of these samples will shed light on both disease mechanisms and potential tests of severity in TBM. Findings could assist tailored and novel interventions to prevent inflammatory reactions in TBM and thus improve outlook for patients.
The team also developed a cell model for laboratory use. This allowed the researchers to study the interaction of human brain cells with tuberculosis infection. As HIV (Human Immunodeficiency Virus) infection increases the chance to contract TB meningitis, the team also studied the effects of the simultaneous presence of both TB and HIV in a controlled system. This work has shed light on the harmful effects of co-infection on the outcome of TB meningitis. It also supports clinical trial findings that show current treatments with anti-inflammatory therapy (corticosteroids) is less effective in these patients.
During this research project, the COVID-19 pandemic took place. The researchers used the opportunity to adapt their model to determine the effect of COVID-19 on the blood brain barrier and central nervous system cells. This has added to an increasing body of literature pointing to significant impact of the pandemic on both neurological and cognitive function.
The funding for this research, provided by Meningitis Now, has resulted in high quality multiple research publications and helped to develop the careers of several early- to mid- career researchers including 3 PhD students. The availability of the funding also made the research team more competitive for further support and the team have now secured funding from the United States government which will allow them to extend their studies.
More information
If you would like more information about this project, or our research in general, please contact research@meningitisnow.org.