Study shows how tuberculosis exploits immune defenses to promote infection

Study shows how tuberculosis exploits immune defenses to promote infection

Scientists have made a discovery that explains why people and animals are so susceptible to tuberculosis (TB) - and the bacteria use a part of the immune system that is supposed to protect against infection.

Despite more than 100 years of research, tuberculosis remains one of the deadliest bacterial infections in humans, causing 1.5 million deaths each year.

Tuberculosis (TB) is caused by the bacterium Mycobacterium tuberculosis (MTB). Infection occurs when the bacteria are inhaled and taken up by specialized immune cells such as macrophages, which recognize MTB and trigger a series of cellular and immune responses. These responses are mediated by receptors – molecules on the surface of immune cells that can recognize microbes. One such receptor is Dectin-1, which is best known for its role in antifungal immunity.

However, MTB has developed a number of strategies to overcome these defenses by manipulating host cells to survive and reproduce. Now an international research collaboration co-led by the University of Exeter has found that MTB survives in its host's cells by targeting Dectin-1. The finding, published in Science Immunology, provides new insight into how tuberculosis causes disease.

Tuberculosis is a leading cause of death worldwide, but we still know very little about how effective it is at causing infections in both humans and animals. “Our discovery of a new mechanism by which Mycobacterium tuberculosis can subvert host immunity is an important step toward understanding the basis of susceptibility to tuberculosis.”

Dr. Max Gutierrez, Francis Crick Institute

In work supported by Wellcome and the Medical Research Council, the team showed that MTB does not protect against infection, as it does with a fungal infection, but rather uses the responses triggered by Dectin-1 to promote its own survival. When this Dectin-1 pathway was missing, both human and mouse cells were able to control MTB infection. In fact, mice lacking Dectin-1 were much more resistant to MTB infection.

The team, consisting of Osaka University, University of Cape Town, Francis Crick Institute and others, also discovered that the bacteria produce a unique molecule called alpha-glucan that targets Dectin-1 and triggers these crucial immune cell responses.

Professor Sho Yamasaki from Osaka University said: "Our results are surprising as Dectin-1 is an important part of the body's defense system to protect against fungal infections. However, we have shown that it is detrimental to MTB infections and actually promotes bacterial survival."

Associate Professor Claire Hoving, UCT, said: "This research is a true international collaboration, with each institution bringing its own area of ​​expertise. It is a fantastic example of the global partnerships required to tackle some of the greatest health challenges of our time."

Professor Gordon Brown, from the University of Exeter's MRC Center for Medical Mycology, said: "This discovery is the first step - and opens the door to exciting new prospects, including the possibility of switching off this receptor in cattle, for example, to make them more resistant to infection."

The study is titled “Mycobacterial α-glucans hijack Dectin-1 to facilitate the survival of intracellular bacteria” and was published in Science Immunology.

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