Accepting PhD Students

PhD projects

Innate Immune immunometabolism: the intersection between metabolism and immunology Suitability: Honours, PhD Project leader: A/Prof Ashley Mansell e: ashley.mansell@hudson.org.au Project description: Recent discoveries have positioned mitochondrial reprogramming by Toll-like receptors (TLRs), at the centre of innate immune inflammation. Immunometabolism describes the interplay between immunological and metabolic processes which are not only critical to the immediate innate immune response to infection, but also the new paradigm of innate memory or training, the concept that myeloid lineage cells can respond more strongly to future challenge via epigenetic reprogramming. We have discovered a role for STAT3 in immunometabolism and how this regulates inflammatory gene induction, mitochondrial health, and metabolism. This project offers the opportunity to explore the molecular dynamics and mechanisms of TLR-induced mitochondrial metabolism, and the temporal influence on transcriptional and epigenetic remodelling using advanced genetic sequencing and metabolomic approaches, in conjunction with novel mouse models of dysfunctional STAT3 signalling and inflammatory disease. Keywords: Innate immunity, inflammation Toll-like receptors, Pattern Recognition Receptors, cell biology, mitochondria, metabolism Inflammasomes and how to drug them to treat emerging pandemic viruses Suitability: Honours, PhD Project leader: A/Prof Ashley Mansell e: ashley.mansell@hudson.org.au Project description: The recent and deadly emergence of SARS CoV 2 (COVID-19) has illustrated how unprepared we are for an emerging infectious disease.There is a desperate need to identify and target how these pathogens induce severe and lethal inflammation during infection. We recently identified and characterised aggregated viral proteins as a novel class of inflammasome activators that induce hyperinflammation characteristic of infections such as avian influenza. We have now identified several proteins that show aggregating potential and inflammasome activation in viruses characterised by excessive inflammation, such as Ebola virus, SARS-coronavirus, dengue virus and picornaviruses. Using novel cell biology methodologies, cell lines, microimaging and gene-deficient mouse models, we will explore the capacity of peptides based on these viral proteins to examine inflammasome activation. This project offers the opportunity to interact with virologists and our collaborators in Bonn, Germany. Keywords: innate immunity, inflammation, emerging infectious diseases, inflammasome, infectious disease

1993 …2020

Research output per year

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Personal profile

Biography

The common factor in all disease

Dr Ashley Mansell views inflammation as the basis of nearly all disease, including cancer, heart disease and diabetes. Inflammation provides the body's first line of defence against disease. Recent discoveries show it is also critical in signalling the body to mount more sophisticated and long-term defences.

When this signalling goes wrong, disease follows.



Ashley studies the immune system and its most fundamental disease-fighting process - how the body first detects it is injured or under attack from microbes.

Despite decades of research, this mechanism was misunderstood until the discovery of a family of receptors - called the Toll-like receptors - that acts as the body's central alarm system. The receptors allow the body to mount a rapid response to disease in the form of inflammation. They also amount to a central mechanism that can determine the outcome of fights against many diseases.

Ashley was working with Professor Luke O'Neill in Dublin, Ireland, when the breakthrough happened. He was using his science degree 'to see the world' and the discovery launched him into a career in this important area of research, including a role with Monash University.

'Inflammation has a lot of firepower when it comes to fighting disease,' Ashley says. 'But it lacks subtlety or specificity. I jokingly call inflammatory responses the shock-and-awe arm of the immune system. It sees the problem and it just responds - a bit blindly and a bit violently - and in the process it causes collateral damage to the body.'

A typical example is the joint pain, headache and fever associated with fighting the influenza virus. But the problem can run deeper. Inflammation is known to overwhelm the body in a runaway reaction that results in auto-inflammatory disorders such as septic shock.

Even more critical is the growing evidence that more sophisticated immune responses, such as those needed to fight cancer, are initiated and guided by inflammation.

By studying inflammation, Ashley and other researchers in his field are shedding new light on why diseases such as cancer escape the immune system's efforts to control them. Inflammation is also a factor in more than 100 auto-immune diseases, including arthritis and asthma. These involve antibodies inappropriately attacking healthy tissue.

For these reasons, Ashley focuses on the genes that control the inflammatory response. Called pattern recognition receptors, they have stirred international interest from laboratories seeking better treatment for patients with specific diseases.

'Globally, we have realised that inflammation is probably the basis of nearly all disease. Cancer, heart disease and obesity included. That means inflammation is an emerging field with the potential to clinically redefine disease.'

Ashley is working in collaboration with a German heart disease laboratory that has detected cholesterol micro-crystals in blocked arteries. The crystals are suspected of triggering disease as they are proving to be potent inducers of self-harming forms of inflammation. Other collaborations see him assisting laboratories working on influenza virus, hepatitis B and asthma.

Internationally, the research is changing how pharmaceutical companies think about disease. Opportunities are being created to develop a new class of therapies and drugs. Such a prospect fascinates Ashley. 'I like to think my research can make a difference, that it can benefit humanity,' he says. 'I may ultimately provide just a small part of a solution. But the idea that I can contribute at all is very motivational.'

Education/Academic qualification

Biochemistry, PhD, Trinity College Dublin

Award Date: 31 Oct 2001

Chemistry, BSc, MONASH UNIVERSITY

Award Date: 18 Nov 1988

Research area keywords

  • Host-Pathogen Interactions
  • Infectious Disease
  • Immunology
  • Molecular Biology
  • Biochemistry
  • Biomedicine
  • Inflammation
  • Underlying Basis of Disease
  • Innate Immunity
  • Regulation of Immune Responses
  • Pattern Recognition Receptors
  • Immunometabolism

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Projects

Research Output

Parsing the IL-37-mediated suppression of inflammasome function

Rudloff, I., Ung, H. K., Dowling, J. K., Mansell, A., D'Andrea, L., Ellisdon, A. M., Whisstock, J., Berger, P., Nold, C. & Nold, M., Jan 2020, In : Cells. 9, 1, 19 p., 178.

Research output: Contribution to journalArticleResearchpeer-review

Open Access
File

Pharmacological inhibition of the NLRP3 inflammasome reduces blood pressure, renal damage, and dysfunction in salt-sensitive hypertension

Krishnan, S. M., Ling, Y. H., Huuskes, B. M., Ferens, D. M., Saini, N., Chan, C. T., Diep, H., Kett, M. M., Samuel, C. S., Kemp-Harper, B. K., Robertson, A. A. B., Cooper, M. A., Peter, K., Latz, E., Mansell, A. S., Sobey, C. G., Drummond, G. R. & Vinh, A., 15 Mar 2019, In : Cardiovascular Research. 115, 4, p. 776-787 12 p.

Research output: Contribution to journalArticleResearchpeer-review

Open Access
File
27 Citations (Scopus)

Repurposing drugs targeting the P2X7 receptor to limit hyperinflammation and disease during influenza virus infection

Rosli, S., Kirby, F. J., Lawlor, K. E., Rainczuk, K., Drummond, G. R., Mansell, A. & Tate, M. D., Oct 2019, In : British Journal of Pharmacology. 176, 19, p. 3834-3844 11 p.

Research output: Contribution to journalArticleResearchpeer-review

Open Access
File
5 Citations (Scopus)

The Single Nucleotide Polymorphism Mal-D96N Mice Provide New Insights into Functionality of Mal in TLR Immune Responses

Dowling, J. K., Tate, M. D., Rosli, S., Bourke, N. M., Bitto, N., Lauterbach, M. A., Cheung, S., Ve, T., Kobe, B., Golenbock, D. & Mansell, A., 15 Apr 2019, In : Journal of Immunology. 202, 8, p. 2384-2396 13 p.

Research output: Contribution to journalArticleResearchpeer-review

1 Citation (Scopus)

An update on the NLRP3 inflammasome and influenza: the road to redemption or perdition?

Tate, M. D. & Mansell, A., 1 Jul 2018, In : Current Opinion in Immunology. 54, p. 80-85 6 p.

Research output: Contribution to journalReview ArticleOtherpeer-review

8 Citations (Scopus)