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Friday February 23, 2024

Congratulations to Dominic De Nardo
2023 ASI Breakthrough Immunology Awardee

We warmly congratulate
Dominic De Nardo
winner of the 2023 ASI Breakthrough Immunology Award.

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Our most prestigious ASI award yet, the ASI Breakthrough Immunology Award supports two outstanding emerging immunologists by providing funding toward their preliminary data for major grant funding applications.
 

I currently lead the Innate Immune Signalling Group in the Department of Biochemistry & Molecular Biology within the Monash Biomedicine Discovery Institute. I am a passionate mid-career researcher with extensive experience in the field of innate immunology, including specific expertise in Toll-like receptor, inflammasome and cGAS-STING signalling pathways. My research focuses on unravelling fundamental mechanisms that govern cellular signalling and protein trafficking responses following activation of innate immune receptors. We aim to understand how these processes contribute to host defence against pathogens, disease pathologies, and anti-tumour immunity.

My journey into innate immunity began during my PhD at the University of Melbourne, where I developed a strong interest in macrophage activation by Toll-like receptors. Subsequently, I underwent postdoctoral training with world renowned innate immunologist Professor Eicke Latz in Bonn, Germany. This enriching experience broadened my expertise and led to the establishment of my junior group under Eicke's guidance. Upon my return to Melbourne in 2014, I joined Professor Seth Masters' lab at The Walter & Eliza Hall Institute. During this time, I acquired new expertise in autoinflammatory conditions resulting from aberrant activation of the immune system. Whilst in Seth’s lab I also initiated research projects to investigate new aspects of STING signalling. In 2019, I was recruited to Professor Ben Kile’s lab at Monash University, fostering a keen interest in live cell imaging to explore mechanisms of STING trafficking. In 2021, I was appointed as an independent Group Leader in the Monash Biomedicine Discovery Institute (BDI). I currently serve as a member on the Monash BDI mid-career researcher committee and in mid-2023 I assumed the role of co-chair for the ASI Innate Immunity Special Interest Group.

Figure 1: ESCRT-dependent STING degradation. Upon activation, STING translocates from the endoplasmic reticulum (ER) to Golgi membranes, where it subsequently buds off on endosomal vesicles. Our recent findings have unveiled the intricacies governing the termination of STING signalling. Specifically, we demonstrated that activated STING undergoes ubiquitination, leading to the recruitment of Endosomal Sorting Complex Required for Transport (ESCRT) proteins. This orchestrated process facilitates STING internalization into multivesicular bodies (MVBs), ultimately paving the way for lysosomal fusion and subsequent STING degradation.

Currently, our group is dedicated to uncovering new mechanisms controlling inflammatory responses driven through activation of cGAS-STING. Microbial or misplaced host dsDNA within the cell cytosol triggers cGAS activity leading to subsequent activation of STING. Upon activation STING is redistributed from the endoplasmic reticulum to the Golgi where it forms larger oligomeric complexes to initiate downstream signalling responses. STING then traffics on endosomal vesicles prior to its degradation within lysosomes. This degradation step is key to ‘turning off’ STING, however, how this happened was unknown. We recently determined that the molecular machinery, known as Endosomal Sorting Complex Required for Transport (ESCRT), packages STING into small compartments, allowing it to be broken down by the lysosome, thus terminating the inflammatory response. Impairment of functional ESCRT activity in macrophages significantly impedes STING degradation, consequently amplifying associated inflammatory responses. (Figure 1; Balka et al. EMBO J 2023). Our discovery has implications for developing targeted therapies in various inflammatory conditions, including autoimmunity and neuroinflammatory diseases.

Our focus has now expanded to examining the contribution of cGAS-STING responses to neuroinflammation in familial forms of frontotemporal dementia (FTD). The ASI Breakthrough Immunology award will support our efforts to explore this area further, enabling us to generate new disease models in human iPSC-derived microglia. I am optimistic that these studies will provide crucial preliminary data, paving the way for future category one funding.

I express my immense gratitude to the ASI for honouring me with this prestigious award. I commend them for providing such a valuable opportunity to specifically support mid-career researchers working in Australian immunology.

De Nardo Lab 2023 (L to R): Dr Tahnee Saunders (Alumni), Dr Kate Balka (Alumin), Dr Dominic De Nardo and Rajan Venkatraman (Current PhD student).

Author: Dominic De Nardo

Disclaimer: The views expressed are those of the author/s and do not necessarily reflect the official policy or position of ASI