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De Nardo Group research

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About Dr Dominic De Nardo

Dr Dominic De Nardo is leader of the Innate Immune Signalling Group in the Department of Biochemistry & Molecular Biology within the Monash Biomedicine Discovery Institute. He has over 12 years of experience in the field of innate immunity with specific expertise in Toll-like receptor (TLR), inflammasome and cGAS-STING signalling pathways.

Dr De Nardo received his PhD in 2009 from the University of Melbourne, Australia, where he developed a keen interest in macrophage activation by the innate immune system. He then undertook postdoctoral training with Professor Eicke Latz at the Institute of Innate Immunity in Bonn, Germany. During his postdoc Dr De Nardo made the seminal discovery of how HDL elicits its anti-inflammatory effects on immune cells (De Nardo et al., Nature Immunology 2014). In 2014 he was awarded the Seymour and Vivian Milstein Young Investigator Award for notable contributions to basic research by the International Cytokine and Interferon Society (ICIS). Dr De Nardo returned to Melbourne in late 2014 to continue his research at the Walter and Eliza Hall Institute of Medical Research, before moving to Monash University in 2019.

Our research

We are examining the molecular processes that control the host innate immune response. To do this we employ a wide range of cell biology, biochemistry and molecular biology techniques combined with high-end imaging and unbiased screening approaches. Our current major research interests are:

  1. Discovery of new molecules and mechanisms regulating innate immune signalling;
  2. Defining fundamental mechanisms that control the cellular signalling and protein trafficking responses downstream of innate immune receptor activation;
  3. Exploring how innate immune processes contribute to host defence against pathogens, disease pathologies and anti-tumour immunity.

Current projects

Visit Dr Dominic De Nardo Monash research profile to see a full listing of current projects.

1. Stimulator of Interferon Genes (STING)-mediated innate immune responses

Pattern recognition receptors (PRRs) have evolved to sense microbial DNA and elicit protective immunity as part of the innate immune system. The major sensor of cytosolic double stranded (ds)DNA is the enzyme cGAS (cyclic GMP-AMP synthase). Upon binding of dsDNA, cGAS produces a cyclic di-nucleotide molecule, cGAMP. STING (Stimulator of Interferon Genes) is then activated by cGAMP to produce key immune mediators, such as interferons (IFNs) and pro-inflammatory cytokines to elicit a protective anti-viral immune response. We investigate the fundamental mechanisms that control the cellular signalling and protein trafficking responses downstream of STING activation.

We recently identified IKKe, as a new molecule in the STING signalling pathway that is able to elicit pro-inflammatory immune responses via the transcription factor, NF-kB (see: Balka et al., Cell Reports 2022). We discovered that IKKe works redundantly along with TBK1, the major effector kinase downstream of STING.  Our findings shed new light on the molecular mechanisms of cGAS-STING signalling and have important implications for the effective therapeutic targeting of STING-related diseases. We are now further examining the roles of IKKe and other key regulators in STING-mediated immune responses.

Figure 1: Summary of findings from Balka et al., Cell Reports 2022.

At steady state, STING is an endoplasmic reticulum (ER) resident protein that exists as a preformed dimer. Upon activation, STING traffics through the ER-Golgi intermediate compartment (ERGIC) and Golgi regions.  Trafficking of STING to the Golgi leads to clustering of STING, providing a platform for the initiation of signal transduction. Post-Golgi, STING is located in endosome and later lysosomal vesicles, which appears important for termination of signalling. We are employing a number of high-end imaging modalities (e.g. Airyscan confocal, Lattice light-sheet) in combination with fluorescent STING reporter systems to examine STING trafficking in both fixed and live immune cells. These high-resolution approaches will illuminate previously unrecognised aspects of STING trafficking and its relation to STING-mediated cellular processes.

Figure 2: STING trafficking. (a)Recognition of dsDNA in the cytosol triggers STING trafficking from the ER, through the Golgi apparatus and into endosomes. Stills from LLSM of macrophages expressing a fluorescent version of STING in the ER (b) when left untreated (UT), or in the Golgi (c) and endosomes (d) following activation. Scale bar, 3 µm.

Figure 3: The redistribution of intracellular STING. Macrophages expressing mRuby3-STING were stimulated for 5 minutes prior to live cell imaging via 3i Marianas spinning disk confocal for a further 10 minutes (total 15 minutes activation time).  mRuby3-STING can be seen throughout the ER network before accumulating into distinct puncta within the Golgi. Scale bar, 5 µm.

2. cGAS-STING in host immunity, autoimmunity and cancer

The activation of the cGAS through sensing of cytoplasmic DNA, is a key driver of immune responses to microbial infection. However, unlike other PRRs, cGAS is not able to discriminate between the origins of dsDNA it encounters. Hence, cGAS-STING can also be activated in response to mislocalised host-derived DNA, such as mitochondrial or nuclear DNA. Not surprisingly, the cGAS-STING pathway is implicated in a number of autoimmune disorders including Aicardi–Goutières syndrome and systemic lupus erythematosus. In addition, specific gain-of-function mutations in STING have been identified that lead to unwarranted immune responses, driving the severe autoinflammatory disease SAVI (STING-associated vasculopathy with onset in infancy). While chronic cGAS-STING activation is detrimental to the host, exogenous application of STING agonists has been exploited to great success in pre-clinical anti-tumour immunotherapies. We are exploring the role of the cGAS-STING pathway in the context of infection, autoimmunity (e.g. Lupus), autoinflammation and anti-cancer immunity.

Figure 4: cGAS-STING in immunity and disease.

3. Myddosome formation and Toll-like receptor (TLR) signalling

TLRs are expressed on plasma and endosomal membranes of innate immune cells, acting as sensors of foreign and inherent danger signals that threaten the host. Upon activation, TLRs facilitate the assembly of large intracellular oligomeric protein complexes, termed ‘Myddosomes’, which initiate key signal transduction pathways.  We have previously identified that the proximal TLR kinase, IRAK4 has a critical scaffold function in Myddosome formation and that its kinase activity is dispensable for Myddosome assembly and the activation of the NF-B and MAPK pathways, but is essential for MyD88-dependent production of inflammatory cytokines (see: De Nardo et al., J Biol Chem 2018). These findings suggest that the scaffold function of IRAK4 may be an attractive target for treating some inflammatory and autoimmune diseases (e.g. using protein degraders). Our group continues to examine the assembly and molecular composition of Myddosomes in response to TLR activation and the mechanisms by which these complexes mediate downstream signalling pathways and immune responses.

Figure 5: The TLR signalling pathways.

Signalling downstream of TLRs is mediated by 2 main adaptor proteins; the MyD88- and/or TRIF-dependent pathways. The recruitment of MyD88 to the TIR domain of TLRs induces IRAK4 and IRAK1/2 binding to form the Myddosome. Activation of TRAF6 downstream of MyD88 leads to the activation of NF-kB, IRF5, and the MAPK pathways, inducing the expression of proinflammatory cytokines. Association of TRIF with TLR3 and internalized TLR4 also leads to expression of proinflammatory cytokines via TRAF6 and RIPK1. TRAF3 also mediates the expression of type I IFNs following activation of the IFN regulatory factors (IRFs). From Balka KR, De Nardo D. J Leukoc Biol. 2019.


We collaborate with many scientists and research organisations around the world. Some of our more significant national and international collaborators are listed below. Click on the map to see the details for each of these collaborators (dive into specific publications and outputs by clicking on the dots).


  • Associate Professor Meredith O’Keefe – Monash Biomedicine Discovery Institute, Monash University
  • Dr Kate Lawlor – Hudson Institute for Medical Research
  • Professor Benjamin Kile – University of Adelaide
  • Associate Professor Michael Gantier – Hudson Institute for Medical Research
  • Associate Professor Seth Masters – The Walter and Eliza Hall Institute of Medical Research
  • Associate Professor Ashley Mansell – Hudson Institute for Medical Research
  • Professor Paul Hertzog – Hudson Institute for Medical Research


  • Professor Eicke Latz – Institute of Innate Immunity, University of Bonn, German
  • Professor Joachim Schultze – LIMES Institute, University of Bonn, Germany
  • Professor Iain Fraser – National Institutes of Health (NIH), Bethesda, USA
  • Professor Felix Meissner – Institute of Innate Immunity, University of Bonn, German
  • Associate Professor Jonathan Miner – Penn Institute for Immunology, University of Pennsylvania, USA

Student research projects

The De Nardo Group offers a variety of Honours, Masters and PhD projects for students interested in joining our group. There are also a number of short term research opportunities available.

Please visit Supervisor Connect to explore the projects currently available in our Lab.

The De Nardo Group offers a variety of Honours, Masters and PhD projects for students interested in joining our group. There are also a number of short-term research opportunities available. You are encouraged to contact Dr Dominic De Nardo regarding potential projects that align with the presented research themes.