Functional relevance of Single Nucleotide Polymorphisms in TLRs and other pattern recognition receptors (Area B)

As numerous examples illustrate the influence of genetic variation in PRR on human disease, we aim to determine the effects of TLR and NLR single-nucleotide polymorphisms (SNPs) on the molecular, cellular, immunological and epidemiologicallevel. Working with several epidemiologists in Germany and abroad - Alexandra Nieters (University of Freiburg; lymphoma), Kari Hemminki/Asta Först (DKFZ Heidelberg; colorectal and breast cancer), Ralf Schumann (sepsis, HIV infection), Thomas Berg( Leipzig University; Hepatitis C virus infection), Adrian Hill (Wellcome Trust Centre for Human Genetics, University of Oxford, UK; invasive pneumococcal disease, bacteraemia, leprosy) – we have identified frequent hypofunctional alleles in TLR5 (Klimosch Cancer Res 2013) and IRAK2 (Wang Hepatology 2015) with disease relevance in colorectal cancer (CRC) and chronic hepatitis C virus infection, respectively. Of note, in both cases, the functional phenotype was not only studied in model systems but could be demonstrated in primary cells from human subjects. In the future we would like these hypofunctional alleles as probes to study the importance of these PRR genes in more detail, for example with regard to their effect on sensing and regulating the intestinal microbiota in affected carriers. This can be achieved in the unique cohort that we have built up in the last years (see below). An additional project in which we hope to investigate the interplay between Innate Immunity and the microbiota is the ImMiGeNe project.