Trinity researchers provide unique human model to help global consortium to unpick the mechanism of human lung immune corruption by the tuberculosis bacterium.
Tuberculosis (TB) is very successful plague. One of the reasons is because the TB bacteria can corrupt a human immune cell (called the pulmonary macrophage) that should otherwise kill the invading pathogen in the lung. Mycobacterium tuberculosis is the germ that causes tuberculosis, and it damages the macrophage by causing lysosomal swelling, deacidification and the accumulation of lipids.
In exciting new work, published in the prestigious Journal of Clinical Investigation, a global consortium of researchers led by Harvard University, has demonstrated that this formidable pathogen has a potent weapon - a lipid known as TbAd - which can corrupt the otherwise successful macrophage response to infection. The Trinity College/St. James Hospital group made a unique contribution to this research because of their exceptional model of TB disease which uses human pulmonary macrophages, donated from consenting patients undergoing bronchoscopy.
Trinity researchers, Professor Joe Keane and Dr Mary O’Sullivan, have shown that after exposure to TbAd, lysosomes swell up in human pulmonary macrophages, which was dose dependent. The Trinity group were among the first to show that the Vitamin A derivative, ATRA, helps the macrophage kill the TB bacillus, and is a promising new therapeutic for TB. In this new report, the group has shown that TbAd interferes with the beneficial effect of ATRA by driving lipid accumulation in macrophages. They even show preliminary results with a chemical that stimulates calcium channels and that serves as an antidote to negative effects of TbAd.
Tuberculosis is re-establishing itself as the biggest infectious killer globally, and Ireland has had a recent increase in multiple-drug-resistant tuberculosis, because of the war crises in Europe. By unpicking the mechanism of how Mycobacterium tuberculosis causes disease, future work may lead to new host-directed therapy for this disease that is entering the post-antibiotic era.
You can read the full paper: 'A terpene nucleoside from M.tuberculosis induces lysosomal lipid storage in foamy macrophages' in the Journal of Clinical Investigation here: https://bit.ly/3SVNi5E
This article was first published on 6 March by Trinity College Dublin.