I run a laboratory at the Walter and Eliza Hall Institute (WEHI) in Melbourne, Australia, and am the Science Director of Mermaid Bio, a new biotech startup with its headquarters in Munich.
Our research focuses on the receptors and molecular signalling networks that cause cell death and inflammation. A particular interest is understanding how the potent pro-inflammatory protein, interleukin-1 (IL-1), is activated and promotes pathology in inflammatory diseases. Understanding how IL-1 activity is controlled will allow the targeted design of next-generation anti-inflammatory therapeutics.
Our recent research revealed molecular links between apoptotic and necroptotic cell death and inflammatory cytokine production, including inflammasome activity. We are continuing to decipher exactly how cell death and inflammation are inextricably linked at the molecular level, with our studies implicating specific cell death modalitites and inflammasome signalling in diseases such as gout, cytokine shock syndromes, cancer and infections such as SARS-Cov-2 and Legionnaires’ disease.
Our ultimate goal is to use genetics, biochemistry, and disease modelling to understand how cell death and inflammation are controlled, and how they influence each other, as a basis for new treatments. To progress this goal and develop therapies against disease-causing proteins WEHI has teamed up with Mermaid Bio. Together, we are developing new “intrabody” therapies – where lipid nanaparticles, such as those used in the COVID-19 vaccines, are being harnessed to delivery mRNAs encoding for therapeutic nanobodies, a type of antibody that can be generated to target any intracellular protein of interest, and which has several advantages when compared to small molecule compounds.
Australia, The University of Melbourne, BSc (Hons), PhD
Science Director, Mermaid Bio GmbH
2022-2026 NHMRC Investigator Grant – Leadership 1. Inflammatory Responses to Programmed Cell Death Signaling.
2020-2023 NHMCR ideas grant (CIA J. Vince) 1183070. Inflammasome activation in autoinflammatory disease.
2020 Perpetual impact grant (Lead Investigator, J. Vince). Discovering new drugs to treat Alzheimer’s and Parkinson’s disease.
2018-2020 NHMRC project grant (CIA J. Vince) 1145788. Unconventional mechanisms for activating the NLRP3 inflammasome.
2016-2018 NHMRC project grant (CIA J. Vince) 1101405. Interleukin-1 biology: mechanisms of regulation, activation and secretion.
2013-2015 NHMRC project grant (CIA J. Vince) 1051210. Regulation of interleukin-1β activation in inflammatory diseases.
2012-2014 New Investigator NHMRC project grant (CIA T. Naderer, CIB J. Vince) 1024829. Diabolic regulation of macrophage cell death pathways by Legionella.
2018-2021 NHMRC CDF Level 2 fellowship. Cell Death and Inflammation.
2013-2016 NHMRC CDF Level 1 fellowship. The role of cell death pathways in inflammation and pathogen infection.
2010-2014 NHMRC Overseas Biomedical Training Fellowship. Reliquished in 2013.
2009-2011 Human Frontiers Long Term Fellowship. Relinquished in 2010.
2009-2010 EMBO Long Term Fellowship. Declined.
Additional Lab Funding
2023 WEHI-Mermaid Bio Funding
2022 Mermaid Bio Funding
2016-2023 Post-Doc Maryam Rashidi; Melbourne University Matheson Centenary Fellowship.
2016-2018 Post-Doc Rebecca Feltham. New Investigator NHMRC Project Grant 1081272: Tipping the inflammatory response of TNF in favour of death.
Caspase-8-driven apoptotic and pyroptotic crosstalk causes cell death and IL-1β release in X-linked inhibitor of apoptosis (XIAP) deficiency.
Hughes SA, Lin M, Weir A, Huang B, Xiong L, Chua NK, Pang J, Santavanond JP, Tixeira R, Doerflinger M, Deng Y, Yu CH, Silke N, Conos SA, Frank D, Simpson DS, Murphy JM, Lawlor KE, Pearson JS, Silke J, Pellegrini M, Herold MJ, Poon IKH, Masters SL, Li M, Tang Q, Zhang Y, Rashidi M, Geng L, Vince JE. EMBO J. 2023 Jan 17:e110468. doi:
Interferon-γ primes macrophages for pathogen ligand-induced killing via a caspase-8 and mitochondrial cell death pathway.
Simpson DS, Pang J, Weir A, Kong IY, Fritsch M, Rashidi M, Cooney JP, Davidson KC, Speir M, Djajawi TM, Hughes S, Mackiewicz L, Dayton M, Anderton H, Doerflinger M, Deng Y, Huang AS, Conos SA, Tye H, Chow SH, Rahman A, Norton RS, Naderer T, Nicholson SE, Burgio G, Man SM, Groom JR, Herold MJ, Hawkins ED, Lawlor KE, Strasser A, Silke J, Pellegrini M, Kashkar H, Feltham R, Vince JE. Immunity. 2022 Mar 8;55(3):423-441.e9. doi: 10.1016/j.immuni.2022.01.003. Epub 2022 Feb 8. PMID: 35139355
Ubiquitylation of RIPK3 beyond-the-RHIM can limit RIPK3 activity and cell death.
Frank D, Garnish S, Sandow JJ, Weir A, Liu L, Clayer E, Meza L, Rashidi M, Cobbold SA, Scutts SR, Doerflinger M, Anderton H, Lawlor KE, Lalaoui N, Keuh AJ, Eng VV, Ambrose, RL, Herold MJ, Samson AL, Feltham RF, Murphy JM, Ebert G, Pearson JS, Vince JE. iScience. 2022. Jun 17;25(7):104632. doi: 10.1016/j.isci.2022.104632. eCollection 2022 Jul 15.
The ubiquitylation of IL-1β limits its cleavage by caspase-1 and targets it for proteasomal degradation.
Vijayaraj SL, Feltham R, Rashidi M, Frank D, Liu Z, Simpson DS, Ebert G, Vince A, Herold MJ, Kueh A, Pearson JS, Dagley LF, Murphy JM, Webb AI, Lawlor KE, Vince JE. Nat Communications. 2021 May 11;12(1):2713. doi: 10.1038/s41467-021-22979-3. PMID: 33976225
The Pyroptotic Cell Death Effector Gasdermin D Is Activated by Gout-Associated Uric Acid Crystals but Is Dispensable for Cell Death and IL-1β Release.
Rashidi M, Simpson DS, Hempel A, Frank D, Petrie E, Vince A, Feltham R, Murphy J, Chatfield SM, Salvesen GS, Murphy JM, Wicks IP, Vince JE. J Immunol. 2019 Aug 1;203(3):736-748. doi: 10.4049/jimmunol.1900228. Epub 2019 Jun 17. PMID: 31209100
The Mitochondrial Apoptotic Effectors BAX/BAK Activate Caspase-3 and -7 to Trigger NLRP3 Inflammasome and Caspase-8 Driven IL-1β Activation.
Vince JE*, De Nardo D, Gao W, Vince AJ, Hall C, McArthur K, Simpson D, Vijayaraj S, Lindqvist LM, Bouillet P, Rizzacasa MA, Man SM, Silke J, Masters SL, Lessene G, Huang DCS, Gray DHD, Kile BT, Shao F, Lawlor K*. Cell Reports. 2018 Nov 27;25(9):2339-2353.e4. doi: 10.1016/j.celrep.2018.10.103. PMID: 30485804
XIAP Loss Triggers RIPK3- and Caspase-8-Driven IL-1β Activation and Cell Death as a Consequence of TLR-MyD88-Induced cIAP1-TRAF2 Degradation.
Lawlor KE, Feltham R, Yabal M, Conos SA, Chen KW, Ziehe S, Graß C, Zhan Y, Nguyen TA, Hall C, Vince AJ, Chatfield SM, D’Silva DB, Pang KC, Schroder K, Silke J, Vaux DL, Jost PJ, Vince JE. Cell Reports. 2017 Jul 18;20(3):668-682. doi: 10.1016/j.celrep.2017.06.073. PMID: 28723569
Active MLKL triggers the NLRP3 inflammasome in a cell-intrinsic manner.
Conos SA, Chem KW, De Nardo D, Hara H, Whitehead L, Núñez G, Masters SL, Murphy JM, Schroder K, Vaux DL, Lawlor KE, Lindqvist LM, Vince JE. Proc Natl Acad Sci U S A. 2017 Feb 7;114(6):E961-E969. PMID: 28096356
Eliminating Legionella by inhibiting BCL-XL to induce macrophage apoptosis.
Speir M, Lawlor KE, Glaser SP, Abraham G, Chow S, Vogrin A, Schulze KE, Schuelein R, O’Reilly LA, Mason K, Hartland EL, Lithgow T, Strasser A, Lessene G, Huang DCS, Vince JE*, Naderer T*. Nature Microbiology. 2016. 1:15034.
RIPK3 promotes cell death and NLRP3 inflammasome activation in the absence of MLKL.
Lawlor KE, Khan N, Mildenhall A, Gerlic M, Croker BA, D’Cruz AA, Hall C, Kaur Spall S, Anderton H, Masters SL, Rashidi M, Wicks IP, Alezander WS, Mitsuuchi Y, Benetatos CA, Condon SM, Wong WW, Silke J, Vaux DL, Vince JE. Nat Communications. 2015 Feb 18;6:6282. PMID: 25693118
Mitochondrial apoptosis is dispensable for NLRP3 inflammasome activation but non-apoptotic caspase-8 is required for inflammasome priming.
Allam R, Lawlor KE, Yu EC, Mildenhall AL, Moujalled DM, Lewis RS, Ke F, Mason KD, White MJ, Stacey KJ, Strasser A, O’Reilly LA, Alexander W, Kile BT, Vaux DL, Vince JE. EMBO Reports. 2014 Jul 2. PMID: 24990442.
Inhibitor of apoptosis proteins limit RIP3 kinase-dependent interleukin-1 activation.
Vince JE, Wong WW, Gentle I, Lawlor KE, Allam R, O’Reilly L, Mason K, Gross O, Ma S, Guarda G, Anderton H, Castillo R, Hacker G, Silke J, Tschopp J. Immunity. 2012 Feb 24;36(2):215-27. PMID: 22365665.
IAP antagonists target cIAP1 to induce TNFalpha-dependent apoptosis.
Vince JE, Wong WW, Khan N, Feltham R, Chau D, Ahmed AU, Benetatos CA, Chunduru SK, Condon SM, McKinlay M, Brink R, Leverkus M, Tergaonkar V, Schneider P, Callus BA, Koentgen F, Vaux DL, Silke J. Cell. 2007 Nov 16;131(4):682-93. PMID: 18022363
Too much cell death has been implicated in many diseases, from autoinflammatory conditions, to infections and cancer. It is now recognised that there is often redundancy and cross-talk in the cell death machinery and, from a therapeutic perspective, several cell death pathways may need to be targeted at the same time. We are developing multi-functional mRNAs that will inhibit several cell death and inflammatory pathways, and intend to deliver these using lipid nanoparticles to treat relevant conditions.
Team members: Dr Deepagan Gopal (and in collaboration with Mermaid Bio. GmbH).
Hepatocellular carcinoma (HCC) represents 85% of liver cancers, is the sixth most common cancer and, globally, is the fourth leading cause of cancer deaths. This project makes use of our cell death and inflammation deficient animals to study the molecular players that promote or inhibit HCC, using a HCC model driven by genetic mutations that cause liver cancer in humans.
Team members: Dr Deepagan Gopal
Cytosolic inflammasome protein complexes drive cell death and inflammation, and while they are key for innate immunity against pathogen infections, their excess activation causes a variety of autoinflammatory conditions. We recently defined a key post-translational modification of the inflammasome-associated cytokine IL-1beta (Nature Communications 2021). This project uses a CRISPR screen to identify the enzymes responsible for IL-1beta modification and will examine their function in inflamamsome-driven disease models. This project may uncover new targets for manipulating inflammasome activity for therapeutic benefit.
Team members: Ashley Weir
Cytokine shock syndromes are frequently lethal conditions often triggered by infectious pathogens in genetically susceptible people (e.g. sepsis, hemophagocytic lymphohistiocytosis, macrophage activation syndrome). We have developed models of cytokine shock syndromes to identify the critical cell death and inflammatory pathways involved, and are using biochemical experiments and genetic manipulation (e.g. cell type-specific targeting) in order to define new therapeutic targets. Potential targets will be tested using new nanobody approaches and, in collaboration with industry, small molecule inhibitors.
Team Members: Farzaneh Shojaee
Host and microbial molecules both contribute to inflammatory bowel disease (IBD). This project examines how the combined actions of inflammatory cytokines and pathogen ligands can combine to cause pathological cell death in IBD using human intestinal organoid models. Using a variety of genetic (CRISPR/Cas9) and pharmacological approaches we are mapping the relevant cell death pathways identified via biochemical and genome-wide transcriptional profiling, and are translating these in vivo using relevant animal models.
Team Members: Jiyi Pang