Cluster I: Pathogen - host cell cross-talk
Infections result as a consequence of specific molecular interactions between a pathogen and its host. Here, we aim to dissect the specific molecular mechanisms and their functional implications employing suitable pathogen models. The retractile type IV pili are broadly abundant among human pathogens and confer their initial attachment to human epithelial cells; this interaction triggers a plethora of host cell reactions, which have implications for the outcome of even fatal infections, such as meningococcal meningitis. Moreover, intracellular bacteria, such as Chlamydiae, make use of a variety of host cell factors and deviate cellular processes in order to ensure their own replication and persistence in the host. By investigating important pathogenesis determinants on both the pathogen and host side, we gain insight into an exciting world of molecular and cellular cross-talk governing infections relevant to human health.
Cluster II: Global analyses of infection
Owing to the intimate co-evolution of pathogens and hosts, the relationship between these poles has reached an unprecedented complexity; the immense diversity of pathogenic microorganisms is echoed by an extremely complex, yet fine-tuned host response system. In order to gain a holistic understanding of the networks conveying the cross-talk between a pathogen and host cells during the course of an infection, we aim to assess the functions of both pathogen and host cell determinants at an unbiased, global scale. This includes loss-of-function studies, transcriptional profiling and comparative protein mass-spectroscopy. Current emphasis is placed on the analysis of crucial host cell determinants by high-throughput, automated RNA interference screens. Using bioinformatics approaches to connect data sets collected from varying perspectives of the pathogen-host cell interaction, we generate a comprehensive and time-resolved view of an infection and define signaling hot-spots and central targets for intervention. Moreover, the discovery of crucial host determinants of infection will extend our understanding of individual susceptibilities to infection in the context of human gene polymorphisms.
Cluster III: RNA and epigenetics – Nucleus biology of infection
Recent discoveries at the forefront of molecular biology have provided a glimpse of the delicate fine-tuning involved in the regulation and epigenetic modulation of human genes. MicroRNAs (miRNA) function in the post-transcriptional regulation and non-protein-coding RNAs (ncRNA) have been implicated in the transcriptional control of gene expression. The function of transcription factors has been found to depend on chromatin structure surrounding target sites and chromatin function in turn is regulated by an array of histone modifications, constituting the histone code. Possibly, with the help of ncRNA and signaling processes, distinct protein complexes are recruited to specific sites of the chromosome. Altogether these factors influence the methylation of the host DNA at distinct regions, e.g. the CpG islands, determining the inheritable epigenetic features of a gene. The most intriguing question arising from the infection point of view is whether pathogens can induce heritable changes in the host cell genome that modulate host cell function in a more permanent way and to the benefit of pathogen persistence. Not surprisingly, pathogens target specific factors towards the nuclei of infected cells. Pathogens may not only manipulate inheritable host cell features but also constitute ideal models to assess the principles of epigenetic gene modulation.
Cluster IV: Translational infection biology
One of the most intriguing connections between chronic infections and human disease is the development of cancer. Helicobacter pylori, one of the world's most common pathogens, is the etiologic agent of gastric cancer; a disease which still affects more than half a million people each year. We are interested in deciphering the mechanisms underlying bacteria induced carcinogenesis in order to develop suitable prevention therapies and to extrapolate to other, yet unproven, infection cancer relationships; candidates include Chlamydia species and Propionibacterium. Moreover, persistent bacterial infections have been implicated in a variety of non-cancer sequels (e.g. neurodegeneration and atherosclerosis), which are gaining increased importance in the context of an aging society. Finally, we pursue ways to apply our research results for the prevention and treatment of infections. This includes the generation of a vaccine against H. pylori and our efforts to establish the targeting of host cell determinants as a novel therapeutic approach for treating infections.