Periodic Reporting for period 2 - CMIL (Crosstalk of Metabolism and Inflammation)
Reporting period: 2017-10-01 to 2019-03-31
Inflammation is a response to noxious stimuli and initiates tissue repair. If resolution fails, however, chronic inflammation develops, which drives tissue damage in many diseases including autoimmunity, cancer and infections. Inflammatory processes are increasingly being appreciated as tightly integrated with metabolic pathways. The molecular crosstalk occurs on different levels including secreted metabolites and cytokines. We hypothesise that this interface of metabolism and inflammation represents a functional rheostat that shapes tissue damage and disease. In this project we analyse the metabolic and inflammatory processes in models of inflammatory diseases such as viral infections and investigate how inflammatory processes affect the metabolism of the host and vice versa. We take a systemic perspective on the entire organism and organ-level changes. We focus on the liver as the central organ for metabolism and a hotspot for receiving, processing and distributing local and systemic signals. Cutting-edge technologies including sequencing, quantitative proteomics and metabolomics will let us create longitudinal multi-dimensional maps of virus-induced alterations. Paired with immunological, virological and pathological analyses, we aim to identify novel regulatory nodes between metabolism and inflammation. Within our systems-wide experiments and supported by preliminary results, we specifically focus on the immunomodulatory roles of bile acids, lipids and other metabolites. These as well as other candidates will be investigated by genetic and pharmacological perturbations in cell culture and in mouse models. Bioinformatics integration of the orthogonal profiling kinetics will reveal novel properties of the molecular networks mediating between metabolism and inflammation. This proposed cross-disciplinary approach aims to improve our understanding of the crosstalk of metabolism and inflammation and has important implications for our mechanistic understanding of our immune system in vivo. In turn this may pave the way for novel targeted therapies against infectious diseases and/or cancer while reducing immunopathological events.
Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far
We performed extensive profiling of liver tissue and serum at different longitudinal time points during chronic viral infection. This included RNA sequencing, quantitative proteomics and metabolomics. Integration of these global data with the course of liver pathology and virus kinetics enabled us to obtain an in-depth picture of virus-induced longitudinal changes in liver tissue as well as in the circulation. We mapped the activation of inflammatory processes including innate immune responses, antigen presentation and adaptive T cell responses and collected evidence for resolution of tissue inflammation at later phases of viral infection. To our surprise we identified wide-spread down regulation of metabolic pathways in the liver as early as two days after infection and persisting thereafter for weeks or even months. In one already published study of metabolic-inflammatory crosstalk, we describe a novel role for the lipid-sensing receptor TREM2 and demonstrate that it modulates hepatitis during viral infection (Kosack L, Gawish R et al. Sci Rep 2017). We also investigated the role of altered concentrations of amino acids in the circulation and dissected a novel role of adipocytes in virus-induced immune-metabolic alterations during infection. Finally, we built a bioinformatic framework which enables us to efficiently integrate data from different biological sources and assess the regulation of inflammatory and metabolic processes in the liver and other organs. Together, we have made considerable progress in dissecting the molecular underpinnings of inflammation and metabolism in different contexts of inflammatory diseases.
Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)
As outlined above the project is well underway and we have several manuscripts lined up which we plan to send to high impact journals. Additional ongoing project-related efforts include the perturbation of other metabolic pathways by means of genetic mouse models as well as comprehensive integration of our findings in order to identify novel molecular mechanisms of inflammation-induced tissue damage. Thereby, next to a better understanding of metabolism and inflammation we aim to identify candidate genes that confer tissue protection and/or improve control of otherwise chronic viruses. Finally, we increasingly recognise common features of infection-induced inflammation and inflammatory changes seen in hepatocellular carcinoma and other types of cancer. This project is therefore expected to contribute to a better understanding of systemic immunometabolic processes with relevance to both infections and cancer.