Forschungszentrum Borstel
Forschungszentrum Borstel

Priority Research Area Asthma and Allergy

Struktural Biochemistry

Projects

For many years, the Division of Structural Biochemistry has been working on topics of inflammatory diseases of allergic and infectious origin, with a particular focus on various aspects of the host-environment interaction with respect to the activation of the innate immune system. In particular, the group has been working on structural analysis, biosynthesis, genetics, and interaction with the host defense of lipopolysaccharides (LPS) from Gram-negative bacteria, of allergy-protective bacteria and substances isolated on farms, and lipids from house dust mites and pollen.

The incidence of allergic diseases has been increasing over the past decades, and such diseases represent one of the important health problems of modern societies, since the means of therapy and prevention of are limited. The effects of existing allergic diseases can be alleviated by a number of available drugs, however, there are no safe causal therapies. The so-called “hygiene hypothesis“ claims that the low stimulation of the early-childhood immune system is due to less infections and exposure to microbes which results in the increase of allergic diseases. Studies of families of farm and non-farm origin supported this hypothesis and proved that school-aged children of farm families suffer much more rarely from rhinitis, asthma and allergic sensitization. It was also shown that a regular contact to cowsheds in the first year of life, together with consumption of raw milk, had the strongest influence on such kind of allergy protection. We have extracted cowshed dust with physiological sodium chloride solution and have shown that this extract efficiently impaired the development of an allergic inflammation and an allergic airway hyper-reactivity in a mouse model.

The Head of Division (Prof. Dr. O. Holst) is continuing the work on the composition of the extract and on the isolation of allergy-protective components in good yields and best purity, and on their structural and functional characterization. In addition, several non-pathogenic bacterial species were isolated on traditionally run farms which currently are investigated with regard to their allergy-protective properties. Also, the Work Group (AG) Structural Microbiology supports investigations on allergic reactions induced by therapeutic antibodies and on the immunogenicity of their N-glycans by sugar analyses.

For many years, the AG Analytics (Dr. K. Duda) has worked on structural analyses of molecules isolated from the bacterial cell envelope (i.e., LPS, lipoteichoic acids, glycolipids), and established a number of protocols on the analysis of high-molecular bacterial polysaccharides. These projects were finished at the end of the year 2015 and the AG left the Division. Since January 2016, Dr. Duda ist the Head of the Junior Research Group Allergobiochemistry (see their homepage), and is working on the structure-function analysis of lipophilic substances from pollen and house dust mite.

In the past, the AG Molecular Microbiology (Dr. U. Mamat) has investigated 3-deoxy-D-manno-oct-2-ulosonic acid(Kdo)-transferases and other enzymes of the LPS biosynthesis, and could e.g., identify the first x-ray structure of a Kdo-transferase. Also, the so-called ClearColi® technology was developed, by which the production of recombinant proteins in endotoxin-free Escherichia coli cells is available. Finally, the group started to work on pathomechanisms of Stenotrophomonas maltophilia, which represents a lung bacterium that can either be commensal or opportunistic pathogenic.

Production of biofilm represents an important virulence factor of S. maltophilia. During this process the bacterium changes to a persisting and flexible pathogen. Based on this fact, biofilm-producing vs. planktonic S. maltophilia strains will be investigated with regard to their expression of signal-transducing proteins, of proteins involved in carbohydrate transport and metabolism, together with experiments on the role of outer membrane vesicles (OMVs), which are produced by S. maltophilia in high amounts and serve as vehicle for the distribution of toxins and other virulence factors. In addition, it will be investigated which RNA molecules are transported in OMVs and whether OMV-associated siRNAs are able to modulate the expression of certain genes in eu- and prokaryotic cells.

S. maltophilia produces various extracellularly active enzymes which probably destroy serum and tissue proteins. This scenario will be investigated in detail.

For a long time, the AG Structural Microbiology (PD Dr. S. Müller-Loennies) has worked on the structural characterisation of antibody (Ab)-ligand-complexes, during which inter alii the structure of an endotoxin-neutralizing Ab complexed with an oligosaccharide of an endotoxin was elucidated for the first time. Furthermore, the structure of an anti-lipid A Ab complexed with ssDNA was characterized. All these studies represent important contributions to an Ab-based therapy of sepsis and help to better understand the process of the production of auto-reactive Ab after infectious diseases.

The AG will investigate molecules of the cell envelope of mycobacteria, in particular i) the structure and function of a cell envelope protein of M. tuberculosis, hypothetically possessing a C-type lectin function, ii) the structure of cell envelope components of a M. tuberculosis strain which lost its virulence after passaging, iii) the cell envelope of M. africanum strains (which are differently recognized in the host), the architecture of which is completely unknown, iv) the protease activity of MycP1 in culture filtrates of virulent mycobacteria, and v) a glucan of lipoarabinomannan-fractions of certain atypical mycobacteria and its biological activity.