Kolloquium der Biologisch-Pharmazeutischen Fakultät

Infection biology and biotechnology of human-pathogenic fungi

Prof. Dr. Axel Brakhage

Molekulare und Angewandte Mikrobiologie, HKI

The dramatic increase of multiresistant bacteria has triggered an intense search for new antibiotics. Most of these compounds are low-molecular-weight natural products, which are important for intercellular communication. Genome mining efforts indicate that the capability of fungi to produce natural products has been substantially underestimated. Many of their biosynthesis gene clusters are silent under standard cultivation conditions. By genetic engineering, we could activate such silent gene clusters, which led to the production of novel compounds. Furthermore, we have discovered that communication between microorganisms represents a physiological trigger for activation of such silent fungal gene clusters. The physical interaction of the fungus Aspergillus nidulans with the soil-dwelling bacterium Streptomyces rapamycinicus, led to the selective activation of silent gene clusters. The bacterium is able to reprogram the fungus by manipulation of its chromatin modification. Knowledge of these regulatory interactions will pave the way to a novel avenue to drug discovery through targeted activation of silent gene clusters.

At the same time fungi can cause life-threatening diseases of humans. Aspergillus fumigatus is the most important air-borne fungal pathogen. A lack of reliable diagnostic tools and effective treatment options results in high mortality rates despite therapy. In my group, we aim at identifying pathogenicity determinants and mechanisms how A. fumigatus can overcome the response of immune effector cells. For this purpose we apply dual transcriptome and (immune)proteome analyses including systems biological analyses with subsequent generation of deletion mutants and their analysis in interaction assays with immune cells like neutrophilic granulocytes and alveolar macrophages and their testing in a mouse infection model. We found that A. fumigatus has developed immune evasion mechanisms which interfere at different levels of the infection process with the response of the human host. These include the prevention of recognition of conidia by special surface molecules, modulation of phagocytosis, intracellular processing, neutrophil extracellular trap formation, and complement activation. Furthermore, we have been working in the identification of fungus-specific T cells that can be used for diagnosis.

References: Bacher et al. (2015) Amer J Respir Crit Care Med; Gsaller et al. (2014) EMBO J; Scharf et al. (2014) PLoS Pathogens; Brakhage (2013) Nature Rev Microbiol; Aimanianda et al. (2009) Nature; Nützmann et al. (2011) PNAS