A ‘Game-Changer’ – Latest TB Research From Trinity

Posted on: 21 March 2016

Researchers from the Trinity College School of Medicine have uncovered a vital role for immune-metabolism in the host response to tuberculosis (TB), with the potential for developing new ‘host-directed’ therapies to treat the deadly infection.

Each year, TB kills 1.5 million people around the world – it is named the leading infectious disease killer globally by the World Health Organisation – and the growing number of multiple drug-resistant cases means that new treatments are desperately needed.

This latest research, led by Dr Laura Gleeson and just published in the Journal of Immunology, reveals that important lung immune cells (called alveolar macrophages) change the way they metabolise sugar when they encounter the bacterium that causes TB (Mycobacterium tuberculosis).

This metabolic change is vital for macrophages to produce the infection-fighting protein interleukin-1beta, and ultimately to kill the bug.

The discovery opens the door to a new realm of potential ‘host-directed’ therapies that could be used to strengthen the immune response to TB, enhancing the outcome of current treatment regimens, and may be particularly useful for targeting drug-resistant strains.

Speaking about the findings Dr Gleeson commented: “We’ve discovered that this metabolic shift is extremely important in the early immune defence that the macrophage mounts against the infection. What we need to do next is identify agents that enhance this metabolic shift to boost the body’s defence – agents that could potentially be administered with current antibiotic regimens to make them more effective at killing the bacterium.

“It’s very exciting – there are many metabolically-targeted drugs that are already licensed for clinical use for other diseases, so there are a lot of different possible agents that can now be investigated, and hopefully translated into improved TB treatments.”

Professor Joe Keane further added: “This is a game-changer when it comes to new approaches to fighting TB. Instead of using antibiotics, which we have pretty much run out of, this discovery opens the door to use a new immune-therapy approach to improve existing treatments.

“There is a range of pre-existing drugs, which we know to be safe, and that can change how our immune system operates. Hence, if we can re-purpose some of these drugs to change metabolism, it may help our immune system fight TB.  And because this is not an antibiotic approach, TB cannot go on to develop resistance to this form of attack.”

Dr Gleeson, a Clinical Research Fellow working with Prof Keane and the TB Immunology Group in the Institute of Molecular Medicine at St James’s Hospital, builds upon the observation by collaborators from Prof Luke O’Neill’s Inflammation Research Group in the Trinity Biomedical Sciences Institute (TBSI) that the bacterial component LPS induces a similar metabolic shift in macrophages taken from mice.

Her work is funded through a Health Professional Fellowship from the Health Research Board and through the Royal City of Dublin Hospital Trust, and relies heavily on patients attending St James’s Hospital for bronchoscopy generously allowing small lung tissue samples to be taken for use in research.

The paper ‘Cutting Edge: Mycobacterium tuberculosis induces aerobic glycolysis in human alveolar macrophages that is required for control of intracellular bacillary replication’ is published in the Journal of Immunology. Link to journal here http://www.jimmunol.org/content/196/6/2444.long