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| Photo Credit: Thirdman |
- Mycobacterium tuberculosis (MTB) Subverts Immune Defense: The bacterium exploits Dectin-1, an immune receptor typically tasked with anti-fungal defense, to facilitate its own survival and replication within host cells rather than being destroyed.
- Mechanism of Action: Research reveals that MTB produces a unique alpha-glucan molecule that specifically targets the Dectin-1 receptor, manipulating host cell responses to create a favorable environment for infection.
- Experimental Evidence: In controlled studies involving human and mouse cells, the absence of the Dectin-1 pathway allowed for better control of the infection; specifically, mice lacking this receptor were found to be significantly more resistant to MTB.
- Global Context: This discovery addresses a critical knowledge gap regarding why humans and animals are highly susceptible to TB, a disease responsible for approximately 1.5 million deaths annually.
- Future Implications: Identifying this pathway offers potential for new therapeutic interventions and preventive strategies, such as genetically modifying livestock to remove the Dectin-1 receptor and increase herd resistance.
Despite more than 100 years of research, tuberculosis remains one of the deadliest bacterial infections in humans, resulting in 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 specialist immune cells, such as macrophages, which recognize MTB and trigger a range 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 anti-fungal immunity.
However, MTB has evolved a range of strategies to overcome these defenses, manipulating host cells so they can survive and replicate. Now, an international research collaboration co-led by the University of Exeter has discovered that MTB survives within the cells of its host by targeting Dectin-1. Published in Science Immunology, the finding gives new insight into how TB takes hold to cause disease.
Dr. Max Gutierrez, of the Francis Crick Institute said: “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. Our discovery of a new mechanism by which Mycobacterium tuberculosis can subvert host immunity is a key step in understanding the basis of susceptibility 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 utilizes the responses triggered by Dectin-1 to drive its own survival. When this Dectin-1 pathway was absent, both human and mouse cells could control MTB infection. Indeed, mice lacking Dectin-1 were much more resistant to MTB infection.
The team, made up of Osaka University, the University of Cape Town and the Francis Crick Institute and others, also discovered that the bacteria produce a unique molecule called alpha-glucan to target Dectin-1 to induce these determinantal immune cell responses.
Professor Sho Yamasaki, Osaka University, said: “Our results are surprising, because Dectin-1 is a key part of the body’s defense system to protect against fungal infections, yet we’ve shown it’s detrimental for MTB infections and actually promotes bacterial survival.”
Associate Professor Claire Hoving, UCT, said: “This research is a true international collaboration, with each institution bringing a distinct area of expertise. It’s a fantastic example of the global partnerships required to tackle some of the greatest health challenges of our time.”
Professor Gordon Brown, of the University of Exeter’s MRC Centre for Medical Mycology, said: “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.”
Published in journal: Science Immunology
Title: Mycobacterial α-glucans hijack dectin-1 to facilitate intracellular bacterial survival
Authors: Shota Torigoe, Sumayah Salie, Roanne Keeton, Beren Aylan, Ben J. Appelmelk, David L. Williams, Douglas W. Lowman, Toshihiko Sugiki, Sohkichi Matsumoto, Akira Kawano, Satoru Mizuno, Kazuhiro Matsuo, Jonas N. Søndergaard, James B. Wing, Maxine A. Höft, Romey Shoesmith, Mthawelanga Ndengane, Anna K. Coussens, Janet A. Willment, Maximiliano G. Gutierrez, Jennifer Claire Hoving, Sho Yamasaki, and Gordon D. Brown
Source/Credit: University of Exeter | Louise Vennells
Reference Number: imgy011026_01