Session 2

Luke O’Neill
School of Biochemistry and Immunology, at Trinity College Dublin, Ireland

A break in endosymbiosis as a basis for inflammatory diseases

Metabolic changes triggered during innate immunity have become a particular focus for researchers interested in inflammation, whilst cancer researchers have had a long standing interest in metabolic disturbance since the days of Warburg.  Mitochondrial disturbance is a feature of inflammatory cells and we have been analysing the Krebs cycle intermediates succinate and fumarate, as well as the Krebs cycle-derived metabolite itaconate, in activated macrophages in response to signalling by Toll-like receptors. Itaconate derivatives are anti-inflammatory and have potential for the treatment of immune and inflammatory diseases. Fumarate is proving to be a very interesting metabolite. It is generated via repression of the enzyme FH and also induction of the argininosuccinate shunt. Fumarate suppresses IL10 production which in turn leads to increased TNF. The decrease in FH however also leads to mitochondrial disturbance, which involves release of double-stranded mitochondrial RNA. This is sensed by the RNA sensors RIG-I, MDA-5 and TLR-7 driving production of Type I Interferons. Metabolites like fumarate are therefore acting as signals and impacting on signalling pathways in unexpected ways. Changes in Krebs cycle and the Electon transport chain also play a role in tumorigenesis and we also have data on a role ROS from Complex III in driving immunosuppressive IL10 in melanoma. These insights are providing a new view of metabolism in immunity and inflammation and might indicate new therapeutic approaches.

Douglas Golenbock
UMass Chan Medical School, Worcester, Massachusetts, USA

Role of the transcription factor cellular nucleic acid-binding protein (CNBP) in malaria

Andrea Ablasser

Global Health Institute, Swiss Federal Institute of Technology Lausanne (EPFL), Switzerland
Swiss Institute for Experimental Cancer Research, Swiss Federal Institute of Technology (EPFL), Switzerland

Sensing DNA as a danger signal through the cGAS-STING pathway

The life of any organism depends on the ability of cells to detect and to respond to pathogens. In order to detect the immense variety of pathogenic entities, the innate immune system of mammals has evolved a range of distinct sensing strategies. One major mechanism is based on the recognition of microbial DNA – an invariant and highly immunogenic pathogen-associated molecular pattern. Host cells, however, contain abundant sources of self-DNA. In the context of cellular damage or metabolic derangement, “out-of-the-context” self-DNA can elicit potentially damaging inflammatory responses. Our research focuses on the so-called cGAS-STING system – an evolutionary highly conserved innate DNA sensing system. On DNA binding, cGAS is activated to produce a second messenger cyclic dinucleotide (cyclic GMP-AMP), which stimulates the adaptor protein STING to induce innate immune responses. While this process was originally discovered as a crucial component of the immune defense against pathogens, recent work has elucidated a pathogenic role for innate DNA sensing in a variety of sterile inflammatory diseases. In this talk I will discuss recent findings on molecular regulation of DNA sensing and highlight opportunities for harnessing cGAS-STING for therapeutic purposes.

Biosketch

Born in Germany, Andrea Ablasser studied Medicine at the Ludwig-Maximilians-University Munich (GER) and earned her MD in 2010. After a postdoctoral work at the University of Bonn (GER), she joined the Swiss Federal Institute of Technology in Lausanne (CH) as Professor in 2014. Amongst several distinctions, Ablasser is a recipient of the William B. Coley Prize, the EMBO Gold Medal, and the National Latsis Prize. Since 2020 she is named „highly Cited Researcher“ (Clarivate Analytics). Ablasser is an elected member of EMBO and the German National Academy of Sciences Leopoldina. In 2018, she co-founded IFM-Due, a company developing immunomodulatory medicines, which was acquired by Novartis in 2024.
Ablasser is studying the mechanisms of innate immunity. She played a major role in deciphering how cells respond to intracellular DNA as a signal of infection via the so-called cGASSTING pathway – a fundamental mechanism of immunity that evolved in bacteria billions of years ago. Apart from its beneficial role in pathogen defense, recognition of DNA is implicated in the pathogenesis of several inflammatory diseases, including neurodegenerative disease and autoimmunity. Ablasser’s current research focuses on understanding molecular rules that govern the termination and control innate immune responses. Using this insight, she is investigating the roles of innate immunity in contexts of disease and exploring novel therapeutic paradigms for cancer immunotherapy.

Gunther Hartmann
Institute of Clinical Chemistry and Clinical Pharmacology with Central Laboratory, University Hospital Bonn, Germany