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22.02.2010

Immune system discovers mould fungi through surface structures

Mould fungus spores, which are found in air aerosols, are constantly being taken up in the air we inhale. As a rule, this poses no danger to healthy people. However, depending on the quantity of spores inhaled and the duration of exposure, mould fungi could possibly lead or contribute to lung diseases and allergies. Dr. Mardas Daneshian and his team at the University of Constance are focusing on the immunostimulatory capacity of fungal spores. The researchers are particularly interested in the interaction of the immune system with the fungal spores and are using an in-vitro lung model for their investigations.

Dr. Mardas Daneshian is a researcher at the University of Constance (© Friedrich Ströbele )

Mould fungi are among the oldest organisms on earth and their ability to degrade means that they make an important contribution to the global substance flow. As shown by fossils, the earliest existence of fungi dates back to around three billion years ago. Fungi and mould fungi in particular specialise in the degradation of dead, organic matter and play a key role in the global ecosystem. "It is estimated that there are around 250,000 different mould fungus species; only a small minority of which specialise in the colonisation of animals and humans," said Dr. Mardas Daneshian, who since 2002, has been part of a project focusing on the immunostimulatory capacity of fungal spores at the Department of Biochemical Pharmacology. Daneshian reports that fungal infections are responsible for around 10 per cent of all blood infections. In German-speaking countries, fungal infections (mycoses) are referred to as "the disease of sick people", because predisposing factors such as anaemia, leukaemia or diabetes favour the colonisation of the human organism.

Mould fungi trigger allergies

Inhaled mould fungi spores pose a particular danger to the respiratory tracts of people with weakened immune systems. However, healthy people are not completely safe from lung diseases caused by fungi. “Previous lung infectious can lead to cavities and scar tissue that can then be colonised by the mould fungi. Aspergillomas can form in lung and other body cavities and, because the immune system is unable to penetrate such cavities, the fungus is able to grow freely by forming a mycelium ball that incorporates dead tissue. The most common symptom of aspergillomas, which need to be removed surgically, is coughing up blood or blood-containing mucus.

Mould fungi are also known to trigger allergies. People with a normal immune system can encounter problems when exposed to mould fungus spores and fungal components. These people can potentially develop type I, III and IV allergies. “At present, 30 fungal structures are known to be highly potent allergens, and about 60 per cent of all atopic people with a tendency to hypersensitivity react to mould fungus allergens as do 5 per cent of all non-atopic people between the ages of 24 and 29,” summarised Daneshian.

Dr. Mardas Daneshian, a scientist from Constance, is looking for targets for new drugs to treat mould fungus-associated respiratory tract diseases. (© Friedrich Ströbele )

Symptoms of allergies triggered by mould fungi include conjunctivitis (runny eyes), rhinitis (runny nose), asthma (narrowing of the airways and distress) as well as allergic alveolitis. "Nowadays, we are aware of a large number of workplace-associated diseases. These diseases are often seen as a combination of type III and IV allergies and are frequently the result of permanent exposure to mould fungi-polluted environments," said Dr. Mardas Daneshian. These diseases, which are referred to as extrinsic-allergic alveolitis (EAA, hypersensitivity pneumonia), include farmer's lung (brought on by the inhalation of biological dust from hay dust or mould spores), cheese washer's disease, bird keepers' lung disease, wood workers' lung or fruit farmers' lung.

Hardly any systematic investigations have been carried out on the critical quantity of spores that needs to be inhaled in order to induce respiratory tract diseases. "Patients with a weakened immune system are well advised to avoid any exposure to microbes, as exposure to a very low number of microorganisms could lead to infection," said the researcher from Constance. The same is true for people suffering from allergies; minimal exposure to allergens can trigger allergic symptoms. According to Dr. Mardas Daneshian, extrinsic allergenic alveolitis and organic dust toxic syndrome are triggered in people who work in environments with a permanent exposure from a million to a billion colony-forming units per cubic metre of air. "As a comparison, the ambient air on a normal summer's day, contains around 10.000 - 100.000 colony-forming units; a cubic metre of air is turned over in a resting state in around 2.5 hours," said the biologist.

Focus on macrophages in the alveoles

Dr. Mardas Daneshian and his team investigated the interplay between mould fungi and the immune system in order to find new starting points for the development of therapeutics against respiratory diseases caused by mould fungi, amongst other things. The researchers focused mainly on the characterisation of the immunostimulatory surface structure of the fungal spores and the description of the role of receptors on the immune cells of the lung, in order to gain a more thorough understanding of inflammatory reactions in the lung. The researchers from Constance used a human whole-blood model to assess the immunostimulation through the spores. They additionally focused on the establishment and description of an in-vitro lung model, which is a co-culture model consisting of two cell lines that represent the macrophages and epithelial cells of the alveoles. The researchers investigated the release of second messenger substances upon the stimulation of spores derived from 44 different mould fungus species.

Fungi modulate the immune system

The researchers used alveolar macrophages, bone marrow cells and blood cells of transgenic mice that lacked certain receptors in their analysis of the receptors. The cells were investigated for their ability to react by releasing second messenger substances when they were stimulated with spores and these cells were then compared with cells in normal mice. The researchers were thus able to find out whether certain receptors were required for the identification of the spores by the immune system or not. “We were able to show that the identification of all mould fungus spores investigated depended on the toll-like receptor 2 (TLR-2) and that almost all fungi modulated the immune system by triggering the release of anti-inflammatory substances,” said Dr. Mardas Daneshian.

The cells’ immune response to the fungi was homogeneous in terms of the release of pro-inflammatory substances. “This suggests that the pro-inflammatory substances are the result of the recognition of similar fungus-like structures, and that the release of anti-inflammatory substances is actively triggered by the fungus,” said Daneshian.

Commonness with bacteria

The investigation of these activities revealed parallels between mould fungi and bacteria in terms of the control of immunostimulatory processes. The fungi possess common surface structures, just like gram-negative and gram-positive bacteria. “During evolution, higher organisms have learned to recognise these structures and interpret them as a signal to generate an immune response in the form of an inflammatory reaction,” said Dr. Mardas Daneshian. This reaction is induced by pro-inflammatory messenger substances released by the immune cells following the recognition of the mould fungi. Following stimulation with mould fungus spores, the pattern of pro-inflammatory substances is similar. Therefore the researchers concluded that fungi also possess such unalterable structures on their surfaces.

The researchers also used enzymes to separate sugar chains from the surface of mould fungi. Spores with a considerably lower number of sugar molecules on their surface led to a significantly stronger immune response. “This leads us to assume that fungal surface sugars also fulfil the purpose of making the fungal immunoactive structures unrecognisable by the human/mammalian immune system,” said Dr. Mardas Daneshian.

The researchers from Constance received the “Umweltpreis 2006” sponsored by Landesbausparkasse Baden-Württemberg and the “Umwelt und Wohnen an der University of Constance“ foundation for their research into the immunostimulatory capacity of mould fungi. In future investigations, Dr. Mardas Daneshian is planning to focus on the investigation and development of methods to replace animal experiments.

A contribution from:
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Michael Statnik - 22.02.2010
© BIOPRO Baden-Württemberg GmbH

Further information:
Dr. Mardas Daneshian
Department of Biochemical Pharmacology
University of Constance
Tel: +49 (0)7531 / 884685
E-mail: mardas.daneshian(at)uni-konstanz.de

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