Title: Improving treatment outcomes in Tuberculous Meningitis
Funder: Meningitis Now

Abstract: 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. 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.

Lay abstract: 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. 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.

Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: INFECTION