Session 1

Kate Fitzgerald

Consequences of STING activation in Health and Disease

UMass Chan Medical School, Worcester, Massachusetts, USA

Abstract

The cGAS-STING Pathway plays a central role in host-defense, anti-tumor immunity as well as Inflammatory Diseases. Sensing of dsDNA leads to activation of cGAS, production of cGAMP which engages STING to turn on type I IFNs and inflammatory cytokine production. Patients afflicted with STING gain-of-function mutations frequently present with debilitating interstitial lung disease (ILD) that is recapitulated in mice expressing the STINGV154M mutation (VM). We have used this model to study the consequences of STING pathway activation in a tissue specific manner including the gut, lung and brain. In the lung, the development of ILD is not dependent on the IRF3-IFNAR signaling pathway. Rather, ILD is dependent on non-hematopoietic cells which ILD and lymphocytes that produce IFN gamma. To identify STING-expressing non-hematopoietic cell-types required for the development of ILD, we used a conditional knock-in (CKI) model and direct expression of the VM allele to hematopoietic cells, fibroblasts, epithelial cells, or endothelial cells. Only endothelial cell-targeted VM expression results in enhanced recruitment of immune cells to the lung associated with elevated chemokine expression and the formation of bronchus-associated lymphoid tissue, as seen in the parental VM strain. These findings reveal the importance of endothelial cells as instigators of STING-driven lung disease. In addition, we also describe consequences of STING activation in microglia cells and our studies that have defined novel strategies to target STING for the treatment of SAVI and related disorders.

Biosketch

Dr. Fitzgerald is Professor and Vice Chair of the Department of Medicine at the University of Massachusetts Chan Medical School. She also serves as Vice Provost for Basic Science Research at the intuitional level. Dr. Fitzgerald is the founding Director of the Program in Innate Immunity and runs an internationally recognized research program focused on the innate immune system aimed at understanding the molecular mechanisms driving inflammatory responses during Infection and in inflammatory diseases. In particular her group has a long standing interest in nucleic acid sensors (especially those that recognize double stranded DNA) and inflammasomes and how these pathways and mechanisms drive innate immune activation and contribute to infectious, inflammatory, and autoimmune diseases.

Dr. Fitzgerald completed all of her education in Ireland. She received her B.Sc. in Biochemistry in 1995 from University College Cork, Ireland and her PhD in Biochemistry in 1999 from Trinity College Dublin, Ireland. After a post-doctoral fellowship at Trinity College Dublin, she joined UMass Chan and has remained at Umass rising through the ranks to a tenured Professor as well as her leadership roles.

Dr. Fitzgerald is an elected member of the Royal Irish Academy, the National Academy of Sciences (USA), the National Academy of Medicine (USA) and the American Academy of Arts and Sciences as well as an elected fellow of the American Society of Microbiology. She is the recipient of several awards including the Thermo-Fischer Meritorious Career Award (from the American Association of Immunology), the Saint Patrick’s Day Medal (from the Irish Government and Science Foundation Ireland) and the Milstein Award for Excellence in Interferon and Cytokine research (from the International Cytokine and Interferon Society), amongst others.

She has extensive service both locally at UMass Chan where she serves as Vice Chair, Research, in the Department of Medicine and as of April 2023, Vice Provost for Basic Science Research. She also has extensive service nationally including service on local and national advisory boards (e.g., Massachusetts Center For Pathogen Readiness, NIAID Board of Scientific Councillors, Burroughs Wellcome Fund Pathogenesis of Infectious Diseases, the Cancer Research Institute and the Smith Odyssey Foundation). She was also the recent past President of the International Cytokine and Interferon Society. She is also a scientific co-founder of a Related Sciences company Danger Bio and serves on the scientific advisory board of a number of biotechs and Pharma.

Gerhard Krönke

Metabolic checkpoints controlling onset and resolution of inflammation

Charité – Universitätsmedizin Berlin, Department of Rheumatology and Clinical Immunology and German Rheumatism Research Centre Berlin, an Institute of the Leibniz Association, Berlin, Germany

Abstract

Increasing evidence highlights the mutual influence between cellular metabolism and the immune response. Recent data from our lab identified distinct metabolic pathways that control both the onset and the resolution of inflammation in response to different cytokines and microenvironmental factors. Identification of underlying mechanisms potentially allows the design of novel strategies for therapeutic intervention during the treatment of immune-mediated inflammatory diseases.  

Biosketch

After graduating from the Medical University of Vienna in 2002, Gerhard Krönke worked as postdoctoral researcher at the Medical University of Vienna (2002-2004) and the University of Virginia, Charlottesville (2004-2006). From 2006-2015 he conducted his clinical training in Internal Medicine and subsequently in Rheumatology at the University Hospital Erlangen, where he worked as Senior Physician at the Department of Internal Medicine 3 from 2012-2023. In 2016, he was appointed Professor of Translational Immunology at the University of Erlangen-Nürnberg. In 2023 he moved to Berlin where he is now serving as director of the Medical Department of Rheumatology and Clinical immunology at the Charité University Hospital Berlin. His research focuses on cellular, molecular and metabolic pathways involved in the maintenance and break of immunological self-tolerance as well as the onset and resolution of inflammation. In particular, he is trying to understand the mechanisms and events leading to the development of inflammatory autoimmune diseases such as rheumatoid arthritis and systemic lupus erythematodes and to develop novel strategies for their diagnosis and treatment. In 2014 he received an ERC Starting grant in 2014 as well as an ERC consolidator grant in 2020 and is currently acting as the spokesperson of the DFG research unit FOR2886 “PANDORA” (Pathways triggering AutoimmuNity and Defining Onset of early Rheumatoid Arthritis).      

Terje Espevik

Inflammatory responses in macrophages are regulated by Rab11-family interacting protein 2 and signalling lymphocyte activation molecule family 1

Terje Espevik, Harald Husebye and Mariia Yurchenko

Centre of Molecular Inflammation Research, Department of Clinical Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway

Abstract

Extensive research on the NLRP3 inflammasome has revealed its central role in antimicrobial defense and in sterile inflammation. The exact mechanisms involved in the priming and activation of the inflammasome are still not clear. However, there is now increasing evidence that membrane trafficking and anchoring at membrane structures such as the trans-Golgi network (TGN) are instrumental steps for NLRP3 inflammasome assembly and activation. The Rab11-family interacting protein 2 (FIP2) is a regulator of intracellular vesicle trafficking and we have shown that FIP2 controls phagocytosis and IFN-b production. Recently, we have found that FIP2 plays a key regulatory role at multiple levels during NLRP3 inflammasome activation in human macrophages. We have demonstrated that the signalling lymphocyte activation molecule family 1 (SLAMF1) is a FIP2 interacting protein and regulates transport of TRAM to E.coli phagosomes acting as an amplifier of the TLR4-TRIF-TRAM signaling pathway. Based on these findings, we developed a SLAMF1-derived peptide, P7, which is linked to a cell-penetrating peptide for intracellular delivery. We found that P7 inhibits the expression and secretion of IFNβ and pro-inflammatory cytokines (TNF, IL-1β, IL-6) induced by TLR4. Also, it prevents death in mice subjected to LPS shock as well as inhibition myocardial infarction in mice. P7 also reduces signaling initiated by endosomal Toll-like receptors like TLR8 and TLR9. The inhibitory effects of the P7 peptide are due to interference with several intracellular protein–protein interactions, including TRAM–SLAMF1, TRAM–FIP2, and TIRAP–MyD88. Overall, P7 peptide has a unique mode of action and demonstrates high efficacy in inhibiting several TLR-mediated responses both in vitro and in vivo.

Biosketch

Terje Espevik is professor of Cell Biology at the Norwegian University of Science and Technology. The strategy of his research is to study cellular and molecular mechanisms that Toll-like receptors, inflammasomes and the complement system are using to mount inflammatory responses. The main goal is to identify new targets for treating inflammation that results in pathology.     

Eicke Latz

German Rheumatism Research Centre Berlin, an Institute of the Leibniz Association, and Charité – Universitätsmedizin Berlin, Berlin, Germany

Biosketch

Prof. Dr. (med.) Eicke Latz studied medicine at the Georg-August University in Göttingen and the Freie Universität Berlin, following which, he worked as an intensive care physician at the Charité Universitätsmedizin. In 2001, he moved to the USA, working as a postdoctoral researcher at Boston University, then at UMass Chan Medical School, where he held his first professorship. In 2010, he returned to Germany and founded the Institute for Innate Immunity at the University Hospital Bonn. He became Scientific Director of the German Rheumatism Research Centre Berlin, a Leibniz Institute, and Professor of Experimental Rheumatology at the Charité Universitätsmedizin Berlin in 2023. His research interests concern how the innate immune system maintains health and under what circumstances it can promote disease. In particular, he investigates the molecular mechanisms that lead to activation or inhibition of the immune system and how these influence the inflammatory reactions in various diseases, such as rheumatic diseases, arteriosclerosis or Alzheimer’s disease.

At the University of Bonn, Prof. Latz was spokesperson of the Collaborative Research Centre “Metaflammation and Cellular Programming” (SFB 1454) and co-spokesperson of the Cluster of Excellence “ImmunoSensation²”. He has co-founded several biotech companies, including IFM Therapeutics (2017), Dioscure Therapeutics (2020),  a ‘Stealth’ biotech’ (2020), and Odyssey Therapeutics (2021), which translate his discoveries into novel therapeutics and preventive approaches. He has been a highly cited scientist in immunology every year since 2014 having published more than 300 publications. Prof. Dr. Latz was elected as a member of the German National Academy of Sciences (Leopoldina) in 2016 and has received a number of prestigious awards, including the Gottfried Wilhelm Leibniz Prize in 2018.