Innate immunity, infection and inflammation

Innate immunity lies at the heart of human disease 

The innate immune system is our body’s first line of defence. When this system senses danger, for example an injury or a pathogen, it responds by initiating inflammation. Macrophages are key cellular components of innate immunity, with important roles in coordinating inflammatory responses and in destroying invading microorganisms.

When their functions are dysregulated, macrophages can trigger inappropriate or excessive inflammation, which is a key driver of many common diseases. The Sweet Group studies the genes and pathways that lead to inappropriate inflammatory responses in macrophages, with the goal of targeting these pathways to develop novel anti-inflammatory therapies.

Macrophages employ an arsenal of weaponry to destroy invading microorganisms, but many important human pathogens can disarm macrophages to establish an infection and cause disease. The Sweet Group also characterizes macrophage antimicrobial responses against bacterial pathogens, so that these pathways can be exploited for the development of new anti-infective agents.

Research overview

An understanding of the molecular processes that control the many functions of macrophages can provide fundamental insights into disease processes.

“We have identified cellular pathways that prevent macrophages from killing some human pathogens, and we are now exploring ways to manipulate the innate immune system to unleash its power to conquer infectious diseases.”

“Instead of using antibiotics, which bacteria can rapidly evolve resistance to, our goal is to defeat specific pathogens by using the bodies own defence system.”

“Innate immunity is a system of incredible influence. If we can understand how this system works, then we can learn how to harness its power to kill infectious agents, and to halt disease-causing inflammation,” said Group Leader Professor Matt Sweet. 

 

Research projects

Innate immunity and inflammation: Cells of the innate immune system, such as macrophages, recognize and respond to danger through several families of pattern recognition receptors, such as the toll-like receptors (TLRs). Dysregulated or inappropriate activation of TLRs and other pattern recognition receptors drives pathology in a range of diseases, including infectious diseases (e.g. sepsis), inflammatory diseases (e.g. inflammatory bowel disease), metabolic diseases (e.g. chronic liver disease), autoimmune diseases (e.g. rheumatoid arthritis), neurodegenerative diseases (e.g. Alzheimer’s disease) and cancer. We study components of TLR and other inflammatory signalling pathways that control activation of macrophages and other innate immune cells. For example, we recently identified a novel transmembrane TLR adaptor protein, which provides specificity to inflammatory cytokine outputs from immune cells. The identification of such molecular pathways can provide opportunities to intervene in inflammation-driven diseases.

Relevant publications:

SCIMP is a transmembrane non-TIR TLR adaptor that promotes proinflammatory cytokine production from macrophages

The E3 ubiquitin ligase RNF144B is LPS-inducible in human, but not mouse, macrophages and promotes inducible IL-1β expression.

TLR3 drives IRF6-dependent IL-23p19 expression and p19/EBI3 heterodimer formation in keratinocytes

 

Innate immunity and infection: A common feature of all pathogens is that they employ strategies to overcome the innate immune system, in order to colonize the host and cause disease. We study how bacterial pathogens such as Salmonella (which causes gastroenteritis and typhoid fever) and uropathogenic E. coli (UPEC, the major cause of urinary tract infections) overcome the innate immune system. For example, we recently showed that Salmonella is able to evade macrophage-mediated zinc toxicity to reside within these cells, and that certain strains of UPEC are able to disarm innate immunity by initiating rapid macrophage cell death. The identification of such evasion mechanisms can lead to the development of novel anti-infective agents.

Relevant publications:

Salmonella employs multiple mechanisms to subvert the TLR-inducible zinc-mediated antimicrobial response of human macrophages

Strain- and host species-specific inflammasome activation, IL-1β release, and cell death in macrophages infected with uropathogenic Escherichia coli

CRIg-expressing peritoneal macrophages are associated with disease severity in patients with cirrhosis and ascites

Conservation and divergence in Toll-like receptor 4-regulated gene expression in primary human versus mouse macrophages

 

Innate immunity and histone deacetylases (HDACs): 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 infection and inflammation, with the goal of manipulating innate immune pathways in therapeutic contexts. For example, we found that HDAC7 (a class IIa HDAC) has pro-inflammatory functions in macrophages, and it thus represents an inflammation target. We also found that HDAC inhibitors promote the clearance of bacterial pathogens from within human macrophages. We are currently developing approaches to selectively target HDACs for anti-inflammatory and anti-infective applications.

Relevant publications:

Histone deacetylases in monocyte/macrophage development, activation and metabolism: refining HDAC targets for inflammatory and infectious diseases

Histone Deacetylase Inhibitors Promote Mitochondrial Reactive Oxygen Species Production and Bacterial Clearance by Human Macrophages

Histone deacetylase 7 promotes Toll-like receptor 4-dependent proinflammatory gene expression in macrophages

Research training opportunities

Research title: Innate Immunity, infection and inflammation

Summary of research interests: Innate immune cells, such as macrophages, express a broad repertoire of pattern recognition receptors that act as danger sensors. For example, members of the Toll-like receptor (TLR) family detect a number of pathogen-associated molecular patterns such as LPS from Gram-negative bacteria. Macrophage activation through TLRs regulates expression of genes involved in antimicrobial responses and inflammation. Thus, TLR signalling is required for effective control of invading microorganisms, but if dysregulated, contributes to acute and chronic inflammatory diseases. We study TLR and inflammasome signalling pathways, as well as the functions of novel TLR-regulated genes in inflammation and in responses to bacterial pathogens (e.g. Salmonella, uropathogenic E. coli). If you have a passion for understanding the processes of innate immunity at the molecular, cellular and organismal level, and are interested in research training opportunities within the Sweet Group, please forward your current CV and an expression of interest to Professor Matt Sweet.

Traineeships, honours and PhD projects include:

  • Macrophage inflammatory pathways and development of anti-inflammatory agents
  • Manipulating antimicrobial pathways for control of intramacrophage pathogens such as Salmonella
  • Regulation of macrophage functions by protein deacetylases
  • Interactions between uropathogenic E. coli and innate immunity
  • The role of zinc trafficking in innate immune-mediated host defence
  • Macrophages and chronic liver disease.

Contact: Professor Matt Sweet

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


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Engagement and impact

Innate immunity and inflammation lies at the heart of most human diseases, and thus an understanding of how innate immunity drives dysregulated inflammation can present opportunities for the development of novel anti-inflammatory agents. Our recent studies have identified a cell surface protein and an intracellular enzyme that drive inflammatory responses of macrophages; both of these molecules represent candidate targets for inflammation-related diseases. We are also collaborating with clinicians to identify inflammatory gene signatures associated with progressive liver fibrosis, in order to develop new biomarkers and therapeutics for chronic liver disease. This is a disease that is rapidly increasing in prevalence globally, and for which no approved therapies exist.

Innate immunity also has a central role in protecting against infectious diseases. Many important human pathogens (e.g. Salmonella, Mycobacterium, HIV) reside within macrophages to avoid immune surveillance. By characterizing antimicrobial pathways that clear reservoirs of intracellular pathogens, we may be able to develop novel anti-infective approaches. For example, we recently identified an enzyme that inhibits macrophage antimicrobial pathways, and we showed that inhibiting this enzyme enabled macrophages to more effectively kill intracellular bacteria.

Relevant links:

http://inflammation.imb.uq.edu.au

https://www.uq.edu.au/news/article/2017/01/latest-research-offers-hope-patients-inflammatory-diseases

Partners and collaborators

Professor Matt Sweet collaborates broadly. Collaborators include:

  • Professor David Fairlie, IMB, UQ
  • Professor Jenny Stow, IMB, UQ
  • Associate Professor Kate Schroder, IMB, UQ
  • Professor Mark Schembri, SCMB, UQ
  • Professor Elizabeth Powell, Department of Gastroenterology and Hepatology, PA Hospital, Brisbane
  • Dr Kate Irvine, Mater Research Institute-UQ
  • Professor Patrick Matthias, Frederick Miescher Institute, Basel, Switzerland
  • Professor Timothy Ravasi, KAUST, Saudi Arabia.

Funding support (current and past) includes National Health and Medical Research Council (NHMRC), The Australian Research Council (ARC), the Australian Infectious Diseases Research Centre and Cancer Council Queensland.
 

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Prof Matt Sweet

Professor Matt Sweet

Group Leader, Cell Biology and Molecular Medicine Division
Director, Centre for Inflammation and Disease Research

  +61 7 3346 2082  
  m.sweet@imb.uq.edu.au
  IMB Researcher Profile
  Centre for Inflammation and Disease Research


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