Innate immunity, infection and inflammation

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 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. Our recent focus has been on understanding metabolic control of macrophage functions and applying this understanding to inflammation-related diseases such as chronic liver disease.

Macrophages also 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, particularly in conditions associated with susceptibility to infections such as Cystic Fibrosis.

Group leader

Professor Matt Sweet

Professor Matt Sweet

Group Leader, Innate immunity, infection and inflammation

+61 7 334 62082
m.sweet@imb.uq.edu.au
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Key breakthroughs & discoveries

Identification of a targetable molecular switch that engages either inflammatory responses or antibacterial responses in macrophages through regulated cell metabolism
Discovery that the pentose phosphate pathway metabolite ribulose-5-phosphate both suppresses inflammatory responses in macrophages and promotes bacterial killing
Characterization of mechanisms used by uropathogenic E. coli to evade macrophage-mediated zinc toxicity
Discovery that macrophage-mediated antibacterial zinc toxicity is defective in people with Cystic Fibrosis.
Identification of gene signatures and pathways associated with chronic liver disease severity, as well as identification of candidate targets for this condition
Characterization of the role of mitochondria and lipid droplets in macrophage inflammatory and antimicrobial responses

Innate immunity and inflammation are central to 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 proteins and metabolites that control macrophage inflammatory responses of macrophages; such molecules represent candidate targets for inflammation-related diseases. We are also collaborating with clinicians to identify inflammatory gene signatures associated with progressive liver fibrosis to develop new biomarkers and therapeutics for chronic liver disease. This is a disease that is rapidly increasing in prevalence globally, and for which new therapies are still needed.

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. We are applying these approaches in conditions in which people are particularly susceptible to infections such as Cystic Fibrosis.

Publications

Partnerships and collaborations

My group collaborates with academics, clinicians and industry to generate knowledge advances in the biomedical sciences and to identify opportunities to understand, diagnose and/or treat immune-regulated disease.

We collaborate with clinicians to identify inflammatory gene signatures associated with progressive liver fibrosis, in order to develop new biomarkers and/or therapeutics for chronic liver disease. This is a disease that is rapidly increasing in prevalence globally, and for which no approved therapies exist.

We also collaborate with clinicians to identify new approaches to combat difficult-to-treat bacterial infections in people vulnerable to infections, for example people with Cystic Fibrosis.

Chronic liver disease:

Elizabeth Powell, clinician scientist (QIMRB, PA Hospital)
Kate Irvine, biomedical scientist (Mater UQ)
Ekihiro Seki, biomedical scientist (Cedars Sinai, LA, USA)

Cystic Fibrosis:

Peter Sly, clinician scientist (Child Health Research Centre)
Paul Robinson (Child Health Research Centre)
Claire Wainwright (Children’s Health Queensland Hopsital and Health Service)
Rachel Thomson (Greenslopes Private Hospital):

Research projects

Targeting mammalian HDACs as an anti-infective strategy

We have found that specific HDAC enzymes constrain macrophage antimicrobial responses, particularly TLR-inducible mitochondrial fission. This project will explore the specific molecular mechanisms by which HDACs constrain macrophage antimicrobial pathways and will investigate novel anti-infective approaches that target HDAC enzymes.

Targeting TLR signalling pathways as an anti-inflammatory strategy

Projects are available to investigate different aspects of TLR-inducible inflammatory pathways in macrophages, particularly the role of immunometabolism, metabolites, and HDAC enzymes.

Characterizing zinc poisoning as an antimicrobial weapon

Innate immune cells deliver toxic levels of zinc to invading microorganisms as an antimicrobial strategy, with zinc-sensitive mutants of many pathogens compromised for defence against innate immune cells. This project will focus on the cellular and molecular mechanisms involved in initiation of this host defence pathway, as well as strategies to amplify this response for anti-infective design.

Organelle-mediated control of innate immunity

In addition to controlling energy production, mitochondria are key regulators of macrophage inflammatory and antimicrobial responses. Lipid droplets, which interact with and regulate mitochondria, have also been linked to specific innate immune functions. This project will explore the control of macrophage inflammatory and antimicrobial responses by mitochondria and lipid droplets.