A ringside seat in the war against infection
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Depletion of macrophages (green cells) after injection of golden staph (orange-red material) into the skin. Credit: Centenary Institute/Nature Immunology
When golden staph enters our skin it can identify the key immune cells and ‘nuke’ our body’s immune response.
Now we know how, thanks to an international research group led by dermatologists from the Centenary Institute and the University of Sydney.
Using state-of-the art microscopy techniques, the team identified the key immune cells that orchestrate the body’s defenders against invading golden staph, and also how the bacteria can target and destroy these cells, circumventing the body’s immune response.
Golden staph (Staphylococcus aureus) is the multi-drug resistant bacterium that is the scourge of hospitals.
The details of the study have been published today in Nature Immunology. It also involved researchers from The Univeristy of Sydney School of Biological Sciences, Monash University, Singapore Immunology Network (A*STAR) and Harvard Medical School.
Wolfgang Weninger. Credit: Centenary Institute
“Staphylococcus aureus kills many, many people around the world. In fact, in the industrialised word, it kills more than tuberculosis and AIDS put together. And the skin is its primary entry point into the body, so it important to understand what happens in the skin,” says Professor Wolfgang Weninger, Head of the Immune Imaging Research Program at Centenary and coordinator of the study.
Using techniques they have developed over the past decade, the research team was able to mark the different cells of the immune system with fluorescent tags of different colours. They then introduced bacteria labelled with similar coloured tags, and observed the unfolding battle live under a multiphoton microscope.
“We can use such imaging to visualise directly what happens under the skin. It allows us to see both invaders and immune cells at the same time, as well as all the structures in the skin, such as blood vessels, lymphatic vessels and hair follicles,” says Professor Weninger.
The initial shock troops of the body’s defence against the invading bacteria are immune cells known as neutrophils. They are stored in and launched from small blood vessels. Large immune cells called macrophages are positioned intermittently on the outside of these blood vessels.
Wolfgang Weninger. Credit: Centenary Institute
The researchers were able to watch as clusters of neutrophils moved out from the blood vessels to fight against the bacteria. About 80 per cent emerged at points close to where macrophages were sitting. The macrophages released proteins which activate the neutrophils and guide them out of the blood vessels, the researchers say.
“But we also found that as soon as the bacteria enter the body, they release a compound called alpha-haemolysin which directly destroys the macrophages, thus disrupting the system that is marshalling the defence forces against them,” says Professor Weninger.
This gives the golden staph time to breed up and overwhelm the immune system. In fact, by the time reinforcements arrive, the tissue surrounding the site of infection has begun to die, diverting the immune system into the task of cleaning up the debris.
This study and visualisation of the war against infection and the opening stages of inflammation builds upon earlier studies in which the research group was able to show how dendritic cells, the immune system’s sentries, guard against invasion by the protozoan parasite, Leishmania.
Such visualisations are also being used to examine how the operation of the immune system changes over time as the body begins to wear out or age.
In March 2014, the Centenary Institute is hosting a multidisciplinary conference on the role of inflammation in disease and ageing. The Future of Experimental Medicine Conference — Inflammation in Disease and Ageing is being organised by Professor Jennifer Gamble and Professor Wolfgang Weninger. Find out more about the conference at: http://femc.mtci.com.au/
Media Contact
- Tamzin Byrne, Science in Public, on 0432 974 400 or tamzin@scienceinpublic.com.au
- Prof Wolfgang Weninger, Head, Immune Imaging Group, Centenary Institute on 0413 092 878 or w.weninger@centenary.org.au
Depletion of macrophages (green cells) after injection of golden staph (orange-red material) into the skin. Credit: Centenary Institute/Nature Immunology
Background Information
Paper Abstract
Transendothelial migration of neutrophils in post-capillary venules is a key event in the inflammatory response against pathogens and tissue damage. The precise regulation of this process is incompletely understood. We report that perivascular macrophages are critical for neutrophil migration into skin infected with the pathogen Staphylococcus aureus. Using multiphoton intravital microscopy we show that neutrophils extravasate from inflamed dermal venules in close physical contact with perivascular macrophages, which are a major source of neutrophil chemoattractants. The virulence factor alpha-hemolysin lyses perivascular macrophages leading to decreased neutrophil transmigration. Our data illustrate a previously unrecognized role for perivascular macrophages in neutrophil recruitment to inflames skin, and indicate that Staphylococcus aureus uses hemolysin-dependent killing of these cells as an immune evasion strategy.
About Wolfgang Weninger
Head, Immune Imaging Group, Centenary Institute
Professor Weninger received his training in clinical dermatology at the Department of Dermatology, University of Vienna Medical School, Vienna, Austria (1992-1999). He then spent four years at Harvard Medical School, US, where he investigated the mechanisms of immune cell migration in vivo. Between 2003-2007, Professor Weninger was a Faculty member at the Wistar Institute and the Department of Dermatology, University of Pennsylvania, US. Recently, he was appointed Chair of the Department of Dermatology, University of Sydney. Professor Weninger’s research focuses on understanding the molecular basis of immune cell migration as well as immune cell interactions with pathogens and cancer cells. At Centenary his group makes use of advanced imaging technology, primarily intravital two-photon microscopy, in a variety of infectious and tumour models.
About the Immune Imagining Group
The Immune Imaging research program comprises four groups whose common feature is that they all employ similar technology – multiphoton microscopes – which can be used to track immune events as they occur in living tissue. This novel imaging approach provides a new way of studying fundamental questions about how the immune system defends us against microbes and cancer cells. Studies of targeted treatments and vaccines also help us understand their mode of action so we can improve therapeutic strategies for patients.
More at: www.centenary.org.au/p/ourresearch/immunity/immuneimaging
About the Centenary Institute
The Centenary Institute is an independent leader in medical research seeking improved treatments and cures for cancer, cardiovascular and infectious diseases. We are working to discover new prevention, early diagnosis and treatment options to enable each generation to live longer, healthier lives than the one before. Centenary’s affiliation with the RPA Hospital and the University of Sydney means that our discoveries can be quickly applied to the fight against disease in the clinic.
More at: www.centenary.org.au and www.centenarynews.org.au