Mal has been dubbed a 'Goldilocks molecule'. Image via Giovana Medeiros
Two Trinity College Dublin researchers have discovered how immune cells respond to TB infection, and it could lead to better treatments.
With the rise of drug-resistant TB, the search is on for a new TB treatment to tackle the bacterial infection.
Now two researchers at Trinity College Dublin have made distinct discoveries about how the immune system fights off the hardy bug, and it could lead to more treatment options down the line.
Shifting immune cells into gear
The bacterium that causes TB, Mycobacterium tuberculosis, is awkward to treat because it grows slowly, it can ‘hide’ in the body for decades on end and it is developing resistance to drugs, explains Dr Laura Gleeson, a Health Research Board clinical research fellow at Trinity College Dublin and St James’s Hospital.
“The treatments we have take a long time and the bugs are developing resistance to the treatment,” she explains. “Current therapies are focused against the bug itself, so we want to find ways to develop therapies that are directed at the host, the human that is infected. The idea is that if you give a therapy that is not directed at the bug, then the bug won’t become resistant to it.”
Gleeson, a medical doctor, is finishing her PhD research with Professor Joe Keane, and has discovered that if frontline defender cells in the lungs called macrophages change metabolic gear, they can fight the TB bacteria more effectively, at least in the lab.
Working with lung macrophages donated by patients during procedures in the hospital, she infected the cells in the lab with the bacteria that cause TB.
Her research found that if the infected macrophage cells underwent a ‘glycolytic shift’ – a change in the way they burn glucose – they could more effectively make a cocktail of infection-fighting biochemicals, including interleukin-1B, and clear the bacteria efficiently.
The findings were published earlier this month in The Journal of Immunology and now the trick will be to find a drug – preferably one that is already approved for human use – that can flip this glycolytic switch in macrophage cells in infected humans and boost their TB-fighting power.
“TB is generally a disease of the poor, so we want to find drugs that are commonly available and preferably off-patent that can alter the metabolism of macrophages and help them to clear the infection,” says Gleeson.
Mal – the Goldilocks molecule
Dr Laura Gleeson and Dr Clíona Ní Cheallaigh
Then, last week, Dr Clíona Ní Cheallaigh, who is also a medical doctor in Keane’s lab and in Professor Ed Lavelle’s lab in the Trinity Biomedical Sciences Institute, had a paper published in the journal Immunity.
Ní Cheallaigh’s work zoned in on a molecule in macrophage cells called Mal, which acts as a signal inside the macrophage, helping it to mobilise forces if there is an infection about.
Mal comes in slightly different versions depending on our genes, and those versions are thought to determine the strength of our immune response in particular diseases, including malaria and TB.
Dubbed a ‘Goldilocks molecule’, it is thought that one variant of Mal results in a weak immune response (porridge too cold, the bacterium survives), another in a rip-roaring immune response (porridge too hot, the human gets damaged) and another in an intermediate immune response (just right, the bug gets squashed but the human doesn’t).
The interferon-gamma connection
Using macrophages from mice and humans, Ní Cheallaigh discovered that an important immune molecule called interferon-gamma, which we produce to fight TB, uses Mal to trigger immune responses in the cells.
This finding could pave the way for more tailored treatments – individual patients could be tested for their Mal ‘type’ and then get the appropriate dose or type of steroid drug that will balance out their Mal-based immune response, explains Ní Cheallaigh.
“You want to bring people to that golden mean where they have an intermediate inflammatory response that is enough to kill the bacteria.”
And now that Ní Cheallaigh has implicated Mal in interferon-gamma pathways in TB, the finding opens up the potential for Mal’s involvement in other conditions that involve interferon-gamma too, like some cancers, eczema and pre-eclampsia in pregnancy.
“It is really exciting, interferon-gamma is involved in lots of other diseases,” explains Ní Cheallaigh. “So we are planning to look in different patient cohorts and try and tease out how the Mal genotype affects the patient’s risk and based on that how best to treat them.”
Both studies were funded by the Health Research Board and, interestingly, build on former discoveries about Mal and glycolytic shifts in macrophages that were made by Irish immunologist Professor Luke O’Neill , who is an author on both papers.
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