Tuberculosis bacterium hijacks immune receptor meant to protect against infection

Researchers have identified a mechanism by which Mycobacterium tuberculosis exploits a key immune receptor to survive inside host cells, offering fresh insight into why tuberculosis remains so effective in humans and animals

Scientists have reported a discovery that has helped to explain why humans and animals are highly susceptible to tuberculosis (TB), revealing that its bacterium co-opts a component of the immune system that normally protects against infection.

TB remains one of the most lethal bacterial diseases worldwide, responsible for around 1.5 million deaths each year. The disease is caused by Mycobacterium tuberculosis (M. tuberculosis), which infects individuals after inhalation of aerosolised bacteria. Once in the lungs, the pathogen is taken up by specialist immune cells, including macrophages, which identify microbial threats and initiate defensive cellular and immune responses.

These responses rely on specific receptors, which are molecules on the surface of immune cells that recognise invading microbes. One such receptor is Dectin-1, which is best known for its role in defence against fungal infection. Under normal circumstances, activation of Dectin-1 contributes to the clearance of fungi by triggering protective immune pathways.

However, M. tuberculosis has evolved strategies to evade and manipulate host defences in order to persist and replicate. A recent international research collaboration co-led by the University of Exeter has now shown that the bacterium survives within host cells by targeting the Dectin-1 receptor. The findings have provided important insight into how TB establishes infection and progresses to disease.

“TB is a major killer worldwide … our discovery of a novel mechanism by which M. tuberculosis is able to subvert host immunity is a key step in understanding the basis of susceptibility to TB,” said Dr Max Gutierrez of the Francis Crick Institute.

In the research which was supported by Wellcome and the UK’s Medical Research Council (MRC), the investigators demonstrated that, rather than protecting against infection as occurs during fungal exposure, the immune responses triggered by Dectin-1 are exploited by M. tuberculosis to promote its own survival.

When this Dectin-1 pathway was absent, both human and mouse immune cells were able to control bacterial infection more effectively. In animal experiments, mice lacking Dectin-1 showed markedly greater resistance to TB.

The collaboration, which involved researchers from Osaka University, Japan, the University of Cape Town, South Africa and the Francis Crick Institute, UK, among other partners, also identified a bacterial molecule responsible for this immune manipulation. The pathogen was shown to produce a distinctive compound, known as alpha-glucan, which interacts directly with Dectin-1 and induces immune responses that ultimately favour bacterial persistence.

“Our results are surprising, because Dectin-1 is a key part of the body’s defence system to protect against fungal infections, yet we have shown it is detrimental for M. tuberculosis infections and actually promotes bacterial survival,” said Professor Sho Yamasaki of Osaka University.

“This research is a true international collaboration, with each institution bringing a distinct area of expertise. It is a strong example of the global partnerships required to tackle some of the greatest health challenges of our time,” said Associate Professor Claire Hoving of the University of Cape Town.

“This discovery is the first step – and opens the door to exciting prospects, including the possibility of disabling this receptor in cattle to increase resistance to infection,” added Professor Gordon Brown of the University of Exeter’s MRC Centre for Medical Mycology indicating that the work could have implications beyond human health.

For further reading please visit: ‘Mycobacterial α-glucans hijack Dectin-1 to facilitate intracellular bacterial survival’