Dr Ashley Mansell - Researcher Profile

Ashley Mansell

Address

Monash Institute of Medical Research
Monash Medical Centre, Clayton

Contact Details

Tel: +61 3 990 24703

Email: Ashley.Mansell@monash.edu


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.”

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

Qualifications

DOCTOR OF PHILOSOPHY
Institution: Trinity College Dublin
Year awarded: 2002
SCIENCE
Institution: Monash University
Year awarded: 1989

Publications

Book Chapters

Mansell, A.S., O'Neill, L.A.J., 2004, Mechanisms of signal transduction and inducible gene expression by the Toll/IL-1 receptor superfamily, in Recent Research Developments in Molecular & Cell Biology, eds SG Pandalai, Research Signpost, Trivandrum India, pp. 297-310.

Mansell, A.S., O'Neill, L.A.J., 2004, Mechanisms of signal transduction and inducible gene expression by the Toll/IL-I receptor superfamily, in Mechanisms of Signal Transduction and INducible Gene Expression 2004, eds M Lienhard Schmitz and Susanne Bacher, Research Signpost, India, pp. 183-199.

Journal Articles

Mittag, D., Varese, N., Scholzen, A., Mansell, A.S., Barker, G., Rice, G., Rolland, J.M., O'Hehir, R.E., 2013, TLR ligands of ryegrass pollen microbial contaminants enhance Th1 and Th2 responses and decreaseinduction of Foxp3hi regulatory T cells, European Journal Of Immunology [P], vol 43, Wiley, Germany, pp. 1-11.

Ve, T., GAY, N., Mansell, A.S., Kobe, B., Kellie, S., 2012, Adaptors in toll-like receptor signaling and their potential as therapeutic targets, Current Drug Targets [P], vol 13, issue 11, Bentham Science Publishers Ltd, Netherlands, pp. 1360-1374.

GreenHill, C., Gould, J.A., Ernst, M.R., Jarnicki, A.G., Hertzog, P.J., Mansell, A.S., Jenkins, B.J., 2012, LPS hypersensitivity of gp130 mutant mice is independent of elevated haemopoietic TLR4 signaling, Immunology And Cell Biology [P], vol 90, issue 5, Nature Publishing Group, United Kingdom, pp. 559-563.

Bozinovski, S., Vlahos, R., Zhang, Y., Lah, L., Seow, H., Mansell, A., Anderson, G., 2011, Carbonylation caused by cigarette smoke extract is associated with defective macrophage immunity, American Journal Of Respiratory Cell And Molecular Biology [P], vol 45, issue 2, American Thoracic Society, United States, pp. 229-236.

Valkov, E., Stamp, A., DiMaio, F., Baker, D., Verstak, B., Roversi, P., Kellie, S., Sweet, M., Mansell, A., Gay, N., Martin, J., Kobe, B., 2011, Crystal structure of Toll-like receptor adaptor MAL/TIRAP reveals the molecular basis for signal transduction and disease protection, Proceedings Of The National Academy Of Sciences Of The United States Of America [P], vol 108, issue 36, National Academy of Sciences, United States, pp. 14879-14884.

Hertzog, P., Mansell, A., van Driel, I., Hartland, E., 2011, Sculpting the immune response to infection, Nature Immunology [P], vol 12, issue 7, Nature Publishing Group, United States, pp. 579-582.

Piganis, R., De Weerd, N., Gould, J., Schindler, C., Mansell, A., Nicholson, S., Hertzog, P., 2011, Suppressor of cytokine signaling (SOCS) 1 inhibits type I interferon (IFN) signaling via the interferon alpha receptor (IFNAR1)-associated tyrosine kinase Tyk2, Journal Of Biological Chemistry [P], vol 286, issue 39, American Society for Biochemistry and Molecular Biology, Inc., United States, pp. 33811-33818.

Lang, T., Lo, C., Skinner, N., Locarnini, S., Visvanathan, K., Mansell, A., 2011, The hepatitis B e antigen (HBeAg) targets and suppresses activation of the toll-like receptor signaling pathway, Journal Of Hepatology [P], vol 55, issue 4, Elsevier BV, Netherlands, pp. 762-769.

Khoo, J., Forster, S., Mansell, A., 2011, Toll-like receptors as interferon-regulated genes and their role in disease, Journal of Interferon and Cytokine Research [P], vol 31, issue 1, Mary Ann Liebert, Inc. Publishers, United States, pp. 13-25.

Greenhill, C., Rose-John, S., Lissilaa, R., Ferlin, W., Ernst, M., Hertzog, P.J., Mansell, A.S., Jenkins, B.J., 2010, IL-6 trans-signaling modulates TLR4-dependent inflammatory responses via STAT3, Journal Of Immunology [P], vol 186, issue 2, American Association of Immunologists, United States, pp. 1199-1208.

Jenkins, K.A., Mansell, A.S., 2010, TIR-containing adaptors in Toll-like receptor signalling, Cytokine [P], vol 49, issue 3, Academic Press, UK, USA, pp. 237-244.

Verstak, B., Nagpal, K., Bottomley, S.P., Golenbock, D.T., Hertzog, P.J., Mansell, A.S., 2009, MyD88 adapter-like (Mal)/TIRAP interaction with TRAF6 is critical for TLR2- and TLR4-mediated NF-kappaB proinflammatory responses, Journal Of Biological Chemistry [P], vol 284, issue 36, The American Society for Biochemistry and Molecular Biology, Inc, United States, pp. 24192-24203.

Thompson, A.J., Colledge, D., Rodgers, S., Wilson, R., Revill, P., Desmond, P., Mansell, A.S., Visvanathan, K., Locarnini, S., 2009, Stimulation of the interleukin-1 receptor and Toll-like receptor 2 inhibits hepatitis B virus replication in hepatoma cell lines in vitro, Antiviral Therapy [P], vol 14, issue 6, International Medical Press, United Kingdom, pp. 797-808.

Phipps, S., Lam, C.E., Kaiko, G.E., Foo, S.Y., Collison, A., Mattes, J., Barry, J., Davidson, S., Oreo, K., Smith, L., Mansell, A.S., Matthaei, K.I., Foster, P.S., 2009, Toll/IL-1 signaling Is critical for house dust mite-specific Th1 and Th2 responses, American Journal of Critical Care [P], vol 179, issue 6, American Association of Critical Care Nurses, USA, pp. 883-893.

Howden, B.P., Smith, D.J., Mansell, A.S., Johnson, P.D.R., Ward, P.B., Stinear, T.P., Davies, J.K., 2008, Different bacterial gene expression patterns and attenuated host immune responses are associated with the evolution of low-level vancomycin resistance during persistent methicillin-resistant Staphylococcus aureus bacteraemia, BMC Microbiology, vol 8, issue 39, BioMed Central Ltd., United Kingdom, pp. 1-14.

Jones, K.L., Mansell, A.S., Patella, S., Scott, B.M., Hedger, M.P., de Kretser, D.M., Phillips, D.J., 2007, Activin A is a critical component of the inflammatory response, and its binding protein, follistatin, reduces mortality in endotoxemia, Proceedings of the National Academy of Sciences of the USA, vol 104, issue 41, Nationall Academy of Sciences, United States, pp. 16239-16244.

Mansell, A., 2007, Life is so much easier for the sea urchin, Immunology And Cell Biology [P], vol 85, issue 6, Nature Publishing Group, United Kingdom, pp. 404-405.

Sweet, M., Mansell, A., Wilson, T., 2007, The Australian Toll-way gets the Nod-meeting report of TLROZ 2007: pattern recognition receptors in immunity and disease, Melbourne, Australia, 16-18th May 2007, Immunology And Cell Biology [P], vol 85, issue 6, Nature Publishing Group, United Kingdom, pp. 401-403.

Lang, T., Mansell, A.S., 2007, The negative regulation of Toll-like receptor and associated pathways., Immunology and Cell Biology, vol 85, issue 6, Nature Publishing Group, New York, USA, pp. 425-434.

Verstak, B., Hertzog, P.J., Mansell, A.S., 2007, Toll-like receptor signalling and the clinical benefits that lie within, Inflammation Research, vol 56, issue 1, Birkhaeuser Verlag AG, Basel, Switzerland, pp. 1-10.

Aeberli, D., Yang, Y.H., Mansell, A.S., Santos, L.L., Leech, M.T., Morand, E.F., 2006, Endogenous macrophage migration inhibitory factor modulates glucocorticoid sensitivity in macrophages via effects on MAP kinase phosphatase-1 and p38 MAP kinase, FEBS Letters, vol 580, issue 3, Elsevier, Amsterdam The Netherlands, pp. 974-981.

Lau, Y., Deliyannis, G., Zeng, W., Mansell, A., Jackson, D., Brown, L., 2006, Lipid-containing mimetics of natural triggers of innate immunity as CTL-inducing influenza vaccines, International Immunology [P], vol 18, issue 12, Oxford University Press, United Kingdom, pp. 1801-1813.

Crack, P.J., Taylor, J.M., Ali, U., Mansell, A.S., Hertzog, P.J., 2006, Potential contribution of NF-kappaB in neuronal cell death in the glutathione peroxidase-1 knockout mouse in response to ischemia-reperfusion injury, Stroke, vol 37, issue 6, Lippincott Williams & Wilkins, Philadelphia USA, pp. 1533-1538.

Mansell, A.S., Smith, R.A., Doyle, S.L., Gray, P., Fenner, J.E., Crack, P.J., Nicholson, S.E., Hilton, D.J., O'Neill, L., Hertzog, P.J., 2006, Suppressor of cytokine signaling 1 negatively regulates Toll-like receptor signaling by mediating Mal degradation, Nature Immunology, vol 7, issue 2, Nature Publishing Group, New York USA, pp. 148-155.

Mansell, A.S., Brint, E., Gould, J.A., O'Neill, L., Hertzog, P.J., 2004, Mal interacts with tumor necrosis factor receptor-associated factor (TRAF)-6 to mediate NF-kB activation by Toll-like receptor (TLR)-2 and TLR4, The Journal of Biological Chemistry, vol 279, issue 36, The American Society for Biochemistry and Molecular Biology,c, USA, pp. 37227-37230.

Mansell, A.S., Khelef, N., Cossart, P., O'Neill, L., 2001, Internalin B Activates nuclear factor-kB via Ras, phosphoinositide 3-kinase, and Akt, The Journal of Biological Chemistry, vol 276, The American Society for Biochemistry and Molecular Biology, UK, pp. 43597-43603.

Fitzgerald, K.A., Palsson-McDermott, E.M., Bowie, A.G., Jefferies, C.A., Mansell, A.S., Brady, G., Brint, E., Dunne, A., Gray, P., Harte, M.T., McMurray, D., Smith, D.E., Sims, J.E., Bird, T.A., O'Neill, L., 2001, Mal(MyD88-adapter-like) is required for toll-like receptor-4 signal transduction, Nature, vol 413, Macmillan Magazines, UK, pp. 78-83.

Mansell, A.S., Reinicke, A., Worrall, M.D., O'Neill, L., 2001, The serine protease inhibitor antihrombin III inhibits LPS-mediated NF-kB activation by TLR-4, FEBS Letters, vol 508, Elsevier Science, pp. 313-317.

Mansell, A.S., Braun, L., Cossart, P., O'Neill, L., 2000, A novel function of inIB from Listeria monocytogenes: activation of NF-k-B in J774 macrophages, Cellular Microbiology, vol 2, issue 2, Blackwell Science, pp. 127-136.

Henry, B.A., Goding, J.W., Alexander, W., Tilbrook, A.J., Canny, B.J., Dunshea, F.R., Rao, A., Mansell, A., Clarke, I.J., 1999, Central Administration of Leptin to Ovariectomized Ewes Inhibits Food Intake without Affecting the Secretion of Hormones from the Pituitary Gland: Evidence for a Dissociation of Effects on Appetite and Neuroendocrine Function, Endocrinology, vol 140:3, Endocrine Society, Bethesda USA, pp. 1175-1182.

Henry, B.A., Goding, J.W., Alexander, W., Tilbrook, A.J., Canny, B., Dunshea, F.R., Rao, A., Mansell, A., Clarke, I.J., 1999, Central administration of leptin to ovariectomised ewes inhibits food intake without affecting the secretion of hormones from the pituitary gland: evidence for a dissociation of effects on appetite and neuroendocrine function, Endocrinology, vol 140, Endocrine Society, Bethesda USA, pp. 1175-1182.

Postgraduate Research Supervisions

Current Supervision

Program of Study:
(DOCTORATE BY RESEARCH).
Thesis Title:
Inflammasome processing of interleukin-1? as a mediator of vascular inflammation in hypertension..
Supervisors:
Mansell, A (Main), Drummond, G (Associate).

Completed Supervision

Student:
Khoo, J.
Program of Study:
The role of Mul1 in the regulation of RIG-I-Like Receptor (RLR) mediated inflammatory and antiviral response. (PHD) 2012.
Supervisors:
Mansell, A (Main), Hertzog, P (Associate), Nagley, P (Associate).
Student:
Lang, T.
Program of Study:
The human hepatitis B e antigen targets and suppresses Toll-like receptor signalling pathways. (PHD) 2011.
Supervisors:
Mansell, A (Main), Hertzog, P (Associate).
Student:
Noppert, S.
Program of Study:
Role of type 1 interferon in LPS-mediated inflammation. (PHD) 2007.
Supervisors:
Deacon, N (Main), Hertzog, P (Associate), Mansell, A (Associate).
Student:
Verstak, B.
Program of Study:
Characterisation of the interaction between Mal and TRAF6 in Toll-like receptor signalling. (PHD) 2008.
Supervisors:
Mansell, A (Main), Hertzog, P (Associate).