AG Prof. J. Mattner

Mikrobiologie

Direktor:
Prof. Dr. med. Christian Bogdan

Background and Research Rationale:

Complex interactions between environmental factors and genetic traits underpin the etiology of infections and immune-mediated diseases as well as the functioning of the immune system. Naturally occurring genetic polymorphisms most likely evolved due to microbial pressure and reveal a consequence of natural selection for enhanced resistance or susceptibility to certain pathogens. Selective microbial pressure to promote functional variations in immune-related genes to resist infectious challenges may add to the pool of variants that alter susceptibility to immune-mediated disorders. We have begun studying the underlying pathways and receptors which regulate host-microbe interactions in models of gastrointestinal infections and immune-mediated pathologies.

Genetic susceptibility to infections and immune-mediated disease

Autoimmune responses and inflammatory processes result from complex interactions of genetic, predisposing factors and distinct environmental cues. Some genetic regions are even associated with susceptibility to multiple infections and/or immune-mediated disorders. However, a protective allele for one disease can represent a susceptibility allele for another. In addition, inflammatory processes are frequently tissue-specific, although (auto-)antigens targeted by the immune system can be expressed throughout the entire body. In this context, our laboratory investigates the genetic and immunological factors that govern the immune responses in the intestine, the pancreas and the liver. Using different genetic approaches and immune- or infection- triggered models, we identified, for example, allelic polymorphisms in an immunoglobulin-like glycoprotein named CD101, which mediated protection to type 1 diabetes, but enhanced susceptibility to infection triggered colitis and liver pathology. Thus, CD101 is an example for an allele, which orchestrates a remarkable switch to tissue-specific pathology once specific bacteria are present in the respective micromilieus. Therefore, we are also currently investigating the contribution of the resident microbiota and other tissues specific factors, such as hypoxia, to these processes.

Recognition of glycosylated antigens

Tissue-resident microbiota promote or inhibit inflammatory and regulatory pathways by signalling through different receptors. Furthermore, the intestinal microbiota prevent pathogens such as Clostridium difficile or Salmonella Typhimurium from colonizing the gastrointestinal tract, a phenomenon known as colonization resistance, due to the competition for nutrients and/or specific receptors and the regulation of the local immune response. Vice versa, intestinal pathogens colonize the gut, replicate therein and/or produce colitis-mediating enterotoxins once the commensal microflora got disrupted. Thus, there exists an increasing need to control the spread of these worldwide emerging infections. Consequently, we are aiming to identify vaccine candidates that prevent the colonization of the intestinal mucosa with Clostridium difficile or Salmonella Typhimurium without disrupting the intestinal microbiota. Due to their well-documented role in the adhesion to host tissues and their structural stability we could identify bacterial surface glycans and glyoclipids as suitable targets for vaccination in this context.

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