<b>Professor Matt Sweet</b><br>
Group Leader, Cell Biology and Molecular Medicine Division<br>
Director, Centre for Inflammation and Disease Research<p>
P: +61 7 3346 2082<br>
E: m.sweet@imb.uq.edu.au<p>
- innate immunity<br>
- inflammatory disease<br>
- rheumatoid arthritis<br>
- atherosclerosis<br>
- infectious disease<br>
- salmonellosis<br>
- urinary tract infections<br>
- cancer
Professor Matt Sweet
Group Leader, Cell Biology and Molecular Medicine Division
Director, Centre for Inflammation and Disease Research

P: +61 7 3346 2082
E: m.sweet@imb.uq.edu.au

- innate immunity
- inflammatory disease
- rheumatoid arthritis
- atherosclerosis
- infectious disease
- salmonellosis
- urinary tract infections
- cancer

Infection and innate immunity

Our bodies have an innate immune system that acts as an alarm system. This system senses danger in the form of infection and/or cell damage, and helps to initiate recovery and repair processes. Macrophages are remarkably dynamic white blood cells that are particularly important cellular components of the innate immune system. These cells are able to directly destroy microbes and also trigger inflammation to prevent infections spreading. However, many important human pathogens, such as HIV and tuberculosis, actually live within macrophages to avoid the immune response. Our lab studies the interactions between macrophages and specific human pathogens, with the goal of understanding how pathogens overcome macrophage functions. Such an understanding will help us to develop new approaches to combat infectious diseases.

Two bacterial pathogens that we are currently studying are Salmonella, which is a bacterium that causes severe gastrointestinal disease leading to high mortality rates around the world; and uropathogenic E. coli (UPEC), which is the major cause of urinary tract infections and is one of the most common infectious diseases.

In 2012 we found that macrophages use zinc to kill bacteria. During the past 12 months, we have built on our understanding of this molecular process, discovering multiple mechanisms that Salmonella uses to evade this particular macrophage response. Since zinc supplementation is used to treat severe diarrheal diseases, but it is not always effective, our findings may help identify new anti-infective approaches. We also identified a specific molecular recognition system that macrophages use to detect and respond to UPEC. This finding may help lead to the development of new ways of combating urinary tract infections.

In addition to providing protection against infectious diseases, the innate immune system can trigger inappropriate inflammation, which contributes to many serious acute and chronic inflammatory diseases such as septic shock, atherosclerosis and rheumatoid arthritis.

Our laboratory also studies the genes and pathways leading to inappropriate inflammatory responses in macrophages.

In 2013, we have continued to discover specific molecular mechanisms that result in excessive macrophage inflammatory responses. We are now working on approaches to block the activity of these pathways, as this may provide new avenues for the development of anti-inflammatory drugs.

Make a difference to Professor Sweet's research by donating today.

Research projects


Cells of the innate immune system such as macrophages play an essential role in providing protection against invading microorganisms, but successful pathogens are able to overcome innate immunity to cause disease. We therefore study macrophage antimicrobial responses, and how the Gram-negative bacterial pathogens Salmonella enterica serovar Typhimurium and uropathogenic E. coli are able to overcome such responses. In contrast to this protective role, innate immunity also drives dysregulated inflammation and pathology in many acute and chronic diseases. Families of pattern recognition receptors, such as the toll-like receptors (TLRs) and nod-like receptors (NLRs), are key initiators of inflammatory responses. We therefore study inflammatory signaling responses downstream of these receptors, and are developing approaches to target innate immune signaling pathways for potential therapeutic applications.

Innate immunity and inflammation

Control of Toll-like Receptor Signaling by Histone Deacetylases (HDAC): HDACs are a family of 18 enzymes that are traditionally considered as epigenetic regulators, but in fact, these enzymes control a diverse array of cellular processes. Inhibitors of classical HDACs (HDAC1-11) are used in the clinic as anti-cancer agents, but also show therapeutic effects in animal models of various inflammation-related diseases. Conversely, HDAC inhibitors also have numerous undesirable properties that limit their potential as anti-inflammatory agents. We study the roles of HDACs in inflammation and in TLR signaling pathways, with the goal of identifying specific HDACs with pro-inflammatory functions. We have found that HDAC7, a class IIa HDAC, is expressed at elevated levels in inflammatory macrophages, and that a specific isoform of this protein (HDAC7u) drives a sub-set of TLR-inducible inflammatory responses via a HIF1alpha-dependent mechanism. We are currently developing approaches to selectively target HDAC7 for anti-inflammatory applications.

For more information see:

Control of Proximal TLR signaling: TLR activation results in the recruitment of specific TIR-containing adaptor proteins (e.g. MyD88, MAL) that relay downstream signaling events (e.g. recruitment and activation of IRAK serine kinases). However, many aspects of proximal TLR signaling are still poorly understood. We study cross-talk between GPCRs and TLR signaling, as well as the roles of novel adaptor proteins in proximal TLR signaling events.

For more information see:

Species Differences in Innate Immune Pathways: With the view that innate immunity is subjected to strong evolutionary pressure from rapidly evolving pathogens, we study species differences in innate immune responses, particularly between human and mouse. We predict that some of these differences will have important consequences for host defence and inflammation. We previously found that, although there is broad conservation between human and mouse transcriptional responses upon TLR activation, a sub-set of TLR target genes show divergent regulation between species. Our analysis of “human-specific” TLR target genes has led us to investigate novel control points for inflammasome responses in human macrophages.

For more information see:

Epithelial Cell-Specific Toll-like Receptor Signaling Pathways: Members of the IRF family of transcription factors impart cell-type specificity to TLR signaling pathways. We have been studying the role of an epithelial cell-specific IRF family member, IRF6, in TLR signaling responses in keratinocytes.

For more information see:

Innate immunity and host defence against bacterial pathogens

Zinc Trafficking in Macrophage Antimicrobial Pathways: Innate immunity regulates metal ion trafficking during host defence. We found that TLR activation of human macrophages results in the delayed accumulation of pools of vesicular zinc within these cells, that this zinc is delivered to E. coli that persists within macrophages to induce a zinc stress response. That is, innate immunity harnesses zinc toxicity for microbial clearance. In contrast, Salmonella is able to avoid being subjected to zinc stress within macrophages through a mechanism dependent upon one of its pathogenicity islands. We are now studying additional mechanisms used by bacterial pathogens to avoid TLR-inducible zinc stress in macrophages, as well as the roles of specific host zinc transporters (e.g. members of the SLC39A and SLC30A families of zinc transporters) in antimicrobial pathways.

For more information see:

Innate Immune Responses to Uropathogenic E. coli (UPEC): UPEC is the major etiological agent of urinary tract infections. Despite the importance of the innate immune system to host defence, the interactions between UPEC and innate immunity are not well understood. Moreover, there is incredible genetic diversity between different clinical isolates of UPEC, and this is likely to impact on innate immune responses against individual UPEC isolates. We have found that some UPEC isolates are able to survive within macrophages, whereas others elicit rapid, pyroptotic cell death. In mouse macrophages, UPEC-triggered IL-1beta maturation and pyroptosis is mediated by NLRP3 and ASC. IL-1beta maturation is also dependent upon NLRP3 in human macrophages, but intriguingly, cell death is independent of this receptor. We are currently mapping the host and bacterial factors responsible for UPEC-triggered human macrophage cell death. For those UPEC strains capable of intramacrophage survival, we are also investigating how specific UPEC genes enable bacterial survival within this niche.

For more information see:

Research training opportunities

Please see IMB's postgraduate website for more information. 

Key publications

View more publications by Professor Sweet via Pubmed or via UQ Reseachers.

Luo L., Wall A.A., Yeo J.C., Condon N.D., Norwood S.J., Schoenwaelder S., Chen K.W., Jackson S., Jenkins B.J., Hartland E.L., Schroder K., Collins B.M., Sweet M.J. and Stow J.L. (2014). Rab8a interacts directly with PI3Kg to modulate TLR4 driven PI3K/mTOR signaling. Nat Commun. 5: 4407.

Shakespear M.R., Hohenhaus D.M., Kelly G.M., Kamal N.A., Gupta P., Labzin L.I., Schroder K., Chan E., Garceau V., Barbero S., Iyer A., Hume D.A., Reid R.C., Irvine K.M., Fairlie D.P. and Sweet M.J. (2013). Histone deacetylase 7 promotes Toll-like Receptor 4-dependent pro-inflammatory gene expression in macrophages. J Biol. Chem. 288: 25362-25374.

Ariffin J.K. and Sweet M.J. (2013). Differences in the repertoire, regulation and function of Toll-like Receptors and inflammasome-forming Nod-like Receptors between human and mouse. Current Opinion in Microbiology. 16: 303-310.

Schroder K., Irvine K.M., Taylor M.S., Bokil N.J., Le Cao K-A., Masterman K., Labzin L.I., Semple C.A., Kapetanovic R., Fairbairn L., Akalin A., Faulkner G.J., Baillie J.K., Gongora M., Daub C.O., Kawaji H., McLachlin G.J., Goldman N., Grimmond S.M., Carninci P., Suzuki H., Hayashizaki Y., Lenhard B., Hume D.A. and Sweet M.J. (2012). Conservation and Divergence in Toll-like Receptor 4-regulated gene expression in primary human versus mouse macrophages. PNAS USA. 109: E944-953.

Achard M.E.S., Stafford S.L., Bokil N.J., Chartres J., Bernhardt P.V., Schembri M.A., Sweet M.J. and McEwan A.G. (2012). Copper redistribution in murine macrophages in response to Salmonella infection. Biochem. J. 15: 51-57.

Shakespear M.R., Halili M.A., Irvine K.M., Fairlie D.P. and Sweet M.J. (2011). Histone Deacetylases as Regulators of Inflammation and Immunity. Trends Immunol. 32: 335-343.

Halili M.A., Andrews M.R., Labzin L.I., Schroder K., Matthias G., Cao C., Lovelace E., Reid R.C., Le G.T., Hume D.A., Irvine K.M., Matthias P., Fairlie D.P. and Sweet M.J. (2010). Differential effects of selective HDAC inhibitors on macrophage inflammatory responses to the Toll-like Receptor 4 agonist LPS. J. Leukoc. Biol. 87: 1103-1114.

Group contacts

Ms Belinda Burgess
Honours student
+61 7 334 62355
Dr Ronan Kapetanovic
Research staff
+61 7 334 62076
+61 7 334 62351
Ms Claudia Stocks
Research higher degree student
+61 7 334 62355
Mr James Curson
Honours student
+61 7 334 62355
Ms Ambika Mosale Venkatesh Murthy
Research higher degree student
+61 7 334 62351
+61 7 334 62355
Professor Matt Sweet
Group leader
+61 7 334 62082
Mr Kaustav Das Gupta
Research higher degree student
+61 7 334 62351
+61 7 334 62355
Dr Divya Ramnath
Research staff
+61 7 334 62071
+61 7 334 62351
Mr Daniel Hohenhaus
Research staff
+61 7 334 62351
+61 7 334 62355
Dr Melanie Shakespear
Research staff
+61 7 334 62076
+61 7 334 62351


On this site