NIH grant for follow-up research on tuberculous meningitis

Reinout van Crevel's group has received a follow-up grant from the US National Institute of Health (NIH). This will enable them to further unravel the disease process of tuberculous meningitis. This should lead to medications with which this life-threatening condition can be better treated in a tailored way.  

Tuberculosis meningitis is the most serious form of this infectious disease. In such a case, tuberculous bacteria invade the brain where they provoke a violent inflammatory reaction, which irrevocably leads to death without treatment. . Even with treatment, many patients die or remain disabled for the rest of their lives. Tuberculous meningitis is only the tip of the tuberculosis iceberg. More than ten million people worldwide suffer from tuberculosis and ten percent die each year. Over one million people. And because tuberculosis patients have much less access to care during the COVID-19 pandemic, annual mortality has increased by a quarter worldwide.

Devastating effects

Reinout van Crevel, an internist-infectiologist at Radboudumc, saw the devastating effects of the disease up close more than 20 years ago when he first went to Indonesia. "Even if they managed to make the difficult diagnosis, they were just as likely to die," he sums up the feeling of helplessness. In the decades that followed, treatment of this group of patients improved only sparsely. "A higher dose of the antibiotic rifampicin reduced mortality. And as standard, patients were given corticosteroids such as prednisone to dampen the intense inflammatory response. That produced improvements, but it was unclear exactly who benefited from corticosteroids."

Changes in metabolism

To come up with a better treatment, Van Crevel is going to study the metabolism in the brains of patients with tuberculous meningitis. He will do this by looking at the cerebrospinal fluid that is taken with an epidural to make the diagnosis. Van Crevel: "The idea behind it is that the tuberculosis bacteria set something in motion in the brain that makes it seriously ill. Such a pathogenic process can, in principle, be read by changes in metabolism. What exactly is that bacterium doing, what biochemical processes does it disrupt, what metabolites - metabolic products - or proteins go up or down, and what genes play a role?" To map the changes at all those levels, Van Crevel had to combine techniques from genomics (genes), metabolomics (metabolites) and proteomics (proteins), among others. With a large grant from the U.S. National Institute of Health (NIH), he got started several years ago in Indonesia and Vietnam.

The role of tryptophan

"Some patients die of TB meningitis despite treatment, others stay alive," says Van Crevel. "In the metabolism of cells in cerebrospinal fluid from both groups, we saw clear differences, one of which was the substance tryptophan. People who died usually had a high, those who survived a low concentration. We know that tryptophan is a nutrient for bacteria, so tuberculosis may strike harder in people with high levels of tryptophan in cerebrospinal fluid. In addition, tryptophan also plays a role in the immune system, in processes that can protect or damage neurons."
A variety of genes probably play a role in tryptophan metabolism. Van Crevel investigated whether genetic variation influences tryptophan levels: "Across the whole genome, we found a number of subtle genetic variants that were strongly associated with the amount of tryptophan in the cerebrospinal fluid. And in a large independent group of patients in whom we had not measured tryptophan, the same genetic characteristics also appeared to predict mortality. Additional evidence that this metabolism is important for the prognosis of patients."

Leaky barrier

Van Crevel's group also saw that a high concentration of matrix metalloproteases - MMPs for short - is a risk factor for a serious, fatal disease outcome. MMPs are enzymes that can break down connective tissue between cells. It is possible that the higher concentration of MMPs in TB meningitis contributes to damage to the blood-brain barrier. "The fundamental study of the disease process then raises the question of whether timely repair of the leaky barrier can improve the situation of these seriously ill patients," says Van Crevel. "That's also what we're going to do."

Tailored immunotherapy

"We already give these patients corticosteroids but by no means all patients respond to them, and in some it even seems harmful. Using cerebrospinal fluid collected during a clinical trial with corticosteroids, we want to find out who should receive this immunotherapy and who should not." And then there is an observation that crops up in the literature with some regularity: aspirins are said to have a protective effect. "There are indications that this is indeed the case," says van Crevel. "Possibly aspirin reduces cerebral infarctions and contributes to the reduction of inflammatory processes. Again with material from a clinical trial, we want to discover how it would work and even more specifically; in which group of patients."
Following on from an earlier large grant, van Crevel has now been awarded another million-dollar grant from the US National Institute of Health. This will allow him to conduct extensive research on inflammation, metabolism and genetic factors not only in adults but also in children in Indonesia and Vietnam. "It should be the prelude to a kind of tailor-made immunotherapy with which the harmful brain inflammations in TB meningitis can be limited. And with that knowledge, eventually the harmful effects of any form of TB as well."
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NIH grant for project '5-year integrative clinical and 'omics' project targeting tuberculous meningitis in Vietnam and Indonesia'

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