In a surprising twist, tuberculosis (TB) bacteria have been found to exploit a key part of the body’s immune system to stay alive and grow inside cells that are supposed to kill them.
This is according to a new international study published in Science Immunology, with major contributions from scientists at the University of Cape Town’s Institute of Infectious Disease and Molecular Medicine (IDM).
Despite more than 100 years of research, TB remains one of the deadliest infectious diseases, killing about 1.5-million people globally each year. The disease is caused by Mycobacterium tuberculosis (MTB), which is inhaled into the lungs and taken up by immune cells called macrophages.
These cells are supposed to destroy harmful bacteria using special receptors that recognise invaders. One of these receptors, known as Dectin-1, usually helps the body fight fungal infections. However, this study found that MTB has developed a strategy that uses a sugar molecule called alpha-glucan to hijack Dectin-1 and avoid being killed.
The team used a combination of genetically modified mice, human immune cells and molecular techniques such as nuclear magnetic resonance (NMR) to track how MTB interacts with Dectin-1.
Instead of helping the immune system, Dectin-1 ends up helping the bacteria survive inside the very cells meant to destroy them.
When scientists removed the Dectin-1 pathway in lab experiments, both human and mouse immune cells were better at controlling the infection. Mice without Dectin-1 were also more resistant to TB.
“In work supported by Wellcome and the Medical Research Council, the team showed that instead of protecting against infection, as occurs during fungal infection, MTB utilises the responses triggered by Dectin-1 to drive its own survival,” said the researchers.
TB is a major killer worldwide, yet we still know very little about how it is so effective at causing infections, in both humans and in animals
— Dr Max Gutierrez of the Francis Crick Institute
The team included scientists from UCT, the University of Exeter, Osaka University, the Francis Crick Institute and others. Together, they discovered that MTB produces a unique molecule, branched alpha-glucan that binds to Dectin-1 and triggers immune responses that actually help the bacteria survive.
“TB is a major killer worldwide, yet we still know very little about how it is so effective at causing infections, in both humans and in animals,” said Dr Max Gutierrez of the Francis Crick Institute.
“Our discovery of a new mechanism by which Mycobacterium tuberculosis is able to subvert host immunity is a key step in understanding the basis of susceptibility to TB.”
“Our results are surprising, because Dectin-1 is a key part of the body’s defence system to protect against fungal infections, yet we’ve shown it’s detrimental for MTB infections and actually promotes bacterial survival,” said Prof Sho Yamasaki of Osaka University.
According to the researchers, findings could open the door to new ways of preventing or treating TB, including the possibility of targeting Dectin-1 to help the body fight back more effectively.
“This discovery is the first step — and opens the door to exciting new prospects including, for example, if we could knock out this receptor in cattle to make them more resistant to infection,” said Prof Gordon Brown of the University of Exeter’s MRC Centre for Medical Mycology.
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