Sensor of the Immune System as Key Point for Fungal Infections and House Dust Allergy

Scientists at the University of Tübingen discover how the body recognizes the alarm signal chitin

dust allergy
3D computer model of the TLR2 receptor (orange), which binds a chitin chain (pink). Here, 5 chitin subunits fit into the binding pocket of TLR2, which allows this receptor to recognize other patterns suggestive of pathogens. The part of the chitin chain that protrudes from the receptor is probably needed to cross-link a second receptor, which leads to the activation of a signal chain and thus to immune and inflammatory reactions. © Alexander Weber

Chitin supports the cell wall of fungi, such as the fungus Aspergillus and the yeast Candidaboth of which can cause dangerous infections in humans. Chitin also forms the outer skeleton of insects and arachnids, which include the mites, and is therefore an important component of house-dust allergens. In mammals themselves, chitin does not occur, so that the human immune system should recognize the natural substance as foreign to the body and react to it with defensive measures. So far, however, a direct binding of chitin to a receptor of the immune system could not be proven. An international research team headed by Professor Alexander Weber from the Interfaculty Institute of Cell Biology at the University of Tübingen has now succeeded in identifying a receptor of the innate immune system as a chitin sensor. The elucidation of chitin-receptor binding provides targets for the development of new therapies for diseases and infections associated with chitin. The results are published in the journalEMBO Reports published.

After cellulose, the main component of the plant cell walls, chitin is considered the second most common natural polysaccharide, also called multiple sugar. Chitin consists of flexible chains or surfaces of the same basic building block, which becomes networked in the cell walls of the mushrooms or in the outer skeleton of animals to stiff structures. Particles of one millimeter do not activate the immune system, but micron-sized particles a thousand times smaller have long been known as immunoactivators. “In previous experiments on the immune detection of chitin, although often micrometer particles were used. However, these were partially contaminated and still larger than a human cell, let alone a tiny single receptor, “says Alexander Weber. Consequently, there was confusion about

In his experiments, the research team used for the first time much smaller chi-tin molecules in a defined composition and size. The experiments revealed that chitin must consist of at least six subunits so that it can activate the receptor of the immune system (Toll-like receptor TLR2) and thus trigger the immune reaction. “We were surprised that chitin chains of five or less building blocks did not trigger an immune response and might even mitigate the immune response,” Weber says. This is the result for the chitin sensors not only in humans and the mouse, “but this size dependence is surprisingly even in plants, as our colleagues in plant biochemistry found”.

Starting point for therapies

In addition to fungal infections, house dust allergy is an economically important disease associated with chitin. The real allergen is the feces of house dust mite, which many people react with airway inflammation to allergic asthma. “Presumably, substances like chitin promote the immune response to these excretory products, much like a vaccine that ‘turns’ the immune system to a specific antigen,” says the scientist. In a fungal infection, it is good if the immune system is activated by chitin. Defined chitin chains could possibly be used in vaccines. Unlike the house dust mite, which is comparatively harmless for humans: The allergic disease is caused by an overreaction of the immune system, to which the chitin contained in house dust contributes. It was to be suppressed. In the experiment, researchers blocked the binding of chitin to the TLR2 receptor, followed by chitin-mediated inflammation, so the immune system was not alerted. “For both purposes, strengthening the immune response against pathogenic fungi as well as the potential prevention of the immune reaction against dust mites, we found an important starting point with the chitin receptor TLR2,” Weber summarizes. However, there is still a long way to go before using this knowledge for targeted therapies. strengthening the immune response against pathogenic fungi as well as the potential prevention of the immune reaction to house dust mites, we have found an important starting point with the chitin receptor TLR2, “Weber summarizes. However, there is still a long way to go before using this knowledge for targeted therapies. strengthening the immune response against pathogenic fungi as well as the potential prevention of the immune reaction to house dust mites, we have found an important starting point with the chitin receptor TLR2, “Weber summarizes. However, there is still a long way to go before using this knowledge for targeted therapies.

dust allergy
Scanning electron micrograph of a human macrophage (scavenger cell) trying to capture a chitin particle in the micrometer range (disk-shaped front). The chitin particle is thus practically as large as the phagocyte and approximately 2000 times larger than the TLR2 receptor (horseshoe-shaped structure in Figure below) itself. Therefore, it was previously unclear whether chitin ever binds directly to a tiny immune receptor such as TLR2 and this activated , © Jürgen Berger / Max Planck Institute for Developmental Biology

Source : University of Tübingen