Innate immunity employs Toll-like receptors (TLRs) and Nod-like receptors (NLRs), both families of so-called pattern recognition receptors (PRRs), to detect a variety of different exogenous and endogenous insults. Exogenous insults include bacteria, viruses and fungi.. Upon engagement of their cognate microbe-derived molecular ligands, PRRs initiate distinct intracellular signalling pathways via receptor-proximal adaptor molecules, and subsequent NF-kB- and IRF-mediated gene transcription activates immediate innate immune responses and primes adaptive immunity. Since the discovery of human TLRs in 1997, other families of mainly cytosolic pattern recognition receptors (PRRs) have been described, for example, the RIG-I-like receptors (RLRs), Nod/NACHT-LRR-like receptors (NLRs) and AIM2-like receptors (ALRs). Together with TLRs, these PRR fulfill the important function of immune surveillance in the innate immune system and mark the first line of immune detection for most microbes. Apart from their role in infection, PRR have also been shown to be vital sensors of the various microbiomes found in different body sites, e.g. the intestine, and to be involved in sensing endogenous danger signals, e.g. accumulated metabolites or tissue breakdown products. As the initial recognition of microbes and endogenous danger signals by PRR has a profound influence on the timing, scale, type and extent of all subsequent innate and adaptive immune responses, PRR are nowadays recognized as pivotal immune regulatory molecules.
Our research focus is dedicated to this important group of sensors. Although our understanding of PRR biology is steadily advancing, the principles of ligand recognition and intracellular signaling still remain poorly known. Little is also know about the differences of these signaling pathways in different human primary cell types or in normal versus transformed cells. Additionally, the functional and epidemiological significance of PRR single-nucleotide polymorphisms (SNPs) remains largely unknown.
Not only can functional PRR SNPs provide insights into PRR biology but in the dawning an age of “personalized medicine” understanding genetic variation at the levels of PRR and immune recognition appears vital. To address some of the open questions surrounding this area of innate immunity, our laboratory is taking a unique approach:
One aim of the lab is to characterize PRR signaling on the molecular and cellular level. To this end we are combining molecular, cell biological and biochemical experiments with in silico methods. Of special interest is how signaling complexes are formed and regulated by post-translational modification. This approach was recently applied to the TLR adaptor molecule MyD88 in which oncogenic mutations contribute to the formation of lymphoma (see also below). Our research showed that mutated MyD88 spontaneously forms signaling complexes, leading to constitutive NF-kB signaling (Avbelj Blood 2014). Similar studies are currently being conducted for the NLRP3 inflammasome and non-conventional members of the NLR family.
After identifying the pharmacologically tractable Bruton’s Tyrosine Kinase (BTK) as a novel regulator of the human NLRP3 inflammasome in myeloid cells (Liu J Allergy Clin Immunol 2017) and platelets (Murthy BBRC 2016), study of the role of BTK in NLRP3 dependent signaling and disease settings will be one of additional main objective in this work area.
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.
Finally, we are interested in the role of PRRs in complex human diseases, studying these receptors in both patient material as well as experimental in vivo models. This work is done in collaboration with clinicians at the University Hospital and several research networks the lab is part of (see Funding page). Current projects include the study of MyD88-IRAK2 signaling in the context of lymphoma, the role of NLRs in colorectal cancer progression, and the role of TLRs in psoriasis.