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A major international collaboration led by Melbourne researchers has discovered that the world’s most widespread malaria parasite infects humans by hijacking a protein the body cannot live without. The researchers were then able to successfully develop antibodies that disabled the parasite from carrying out this activity.
The study, led by the Walter and Eliza Hall Institute’s Associate Professor Wai-Hong Tham and Dr Jakub Gruszczyk, found that the deadly malaria parasite Plasmodium vivax (P. vivax) causes infection through latching onto the human transferrin receptor protein, which is crucial for iron delivery into the body’s young red blood cells.
Published today in Science, the discovery has solved a mystery that researchers have been grappling with for decades.
The MX and SAXS beamline staff at the Australian Synchrotron assisted with data collection.
Associate Professor Tham, who is also a HHMI-Wellcome International Research Scholar, said the collective efforts of teams from Australia, New Zealand, Singapore, Thailand, United Kingdom, United States, Brazil and Germany had brought the world closer to a potential effective vaccine against P.vivax malaria.
“P. vivax currently inflicts a huge burden on global health. It is the most common malaria parasite in countries outside of Africa, with more than 16 million clinical cases recorded each year.
“The parasite can lie dormant in the liver for months on end without causing any symptoms, which makes it very sneaky and difficult to treat,” Associate Professor Tham said.
“We now know that P. vivax is hijacking the human transferrin receptor which is essential for transporting iron into the body’s young red blood cells.
“Being able to stop P. vivax from latching onto this receptor and infliltrating the blood is a major breakthrough and important step towards malaria elimination,” she said.
Dr Gruszczyk said once the teams understood how the parasite was gaining entry into the cells, they were able to design antibodies to block the mode of access.
“Using the Australian Synchrotron in Melbourne, we generated a 3D map of the parasite protein which is the mechanism P. vivax uses to latch onto the human transferrin receptor and enter the young red blood cells.
“This map provided an unprecedented view of the parasite protein’s shape, which guided the design of antibodies to block P. vivax from gaining entry into the human cells,” Dr Gruszczyk said.
Associate Professor Tham said they were thrilled to see the antibodies successfully block P. vivax invasion using parasites from both Thailand and Brazil. “We are now looking to include collaborative partners in the Pacific, so we can further test the effectiveness of our antibodies,” she said.
Study collaborator Dr Jonathan Abraham from Harvard University said the results of the new study aligned with a growing body of evidence that could be used to target multiple infectious diseases.
“Transferrin receptor is also co-opted by five viruses that cause Ebola-like diseases in South America. These diseases are known as New World haemorrhagic fevers.
“Our increasing understanding of how several pathogens are taking advantage of transferrin receptor, means we are getting closer to disrupting infection for a number of deadly diseases,” Dr Abraham said.
The research was funded by the Australian National Health and Medical Research Council, Australian Research Council, National Institutes of Health, Howard Hughes Medical Institute (HHMI), the Wellcome Trust, Canadian Institutes of Health, Singapore National Medical Research Council, Agency for Science, Technology and Research, the Marsden Fund, Walter and Eliza Hall Institute Speedy Innovation Grant, the Drakensberg Trust and the Victorian Government Operational Infrastructure Support Program.
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Australian Synchrotron X-ray and infrared imaging techniques have been used in a powerful combined approach to characterise the composition of amyloid plaques that are associated with Alzheimer’s disease.
Alzheimer’s disease is major international health problem that accounts for 50-75 per cent of all cases of dementia in Australia. More than 400,000 Australians are living with dementia and it is the second leading cause of death.
Amyloid plaques are complex protein fragments which accumulate between nerve cells in the brain and may destroy connections between them, and are hallmarks of Alzheimer’s disease.
“However, it is still not known if the plaques cause Alzheimer’s or whether the Alzheimer’s causes their formation, which is why we need to improve our understanding of protein structures within plaques, and the molecular and elemental composition of tissue surrounding the plaques“ said Dr Mark Hackett of Curtin University, who led the research.
The study was published earlier in the year in Biochemistry.
As very few methods provide sufficient chemical information to study the composition and distribution of the plaques in excised tissue, the investigators decided to combine Synchrotron spectroscopic techniques with additional imaging methods, Raman spectroscopy and fluorescence microscopy.
“It is something that really hasn’t been done before in Australia and demonstrates the power of the approach” said Australian Synchrotron instrument scientist Dr David Paterson. He and Dr Mark Tobin of the Synchrotron were among a large team of collaborators from Curtin University, the University of Saskatchewan and The University of Adelaide.
Metals have long been associated with amyloid plaques and Alzheimer’s, and a number of leading international research groups have used synchrotron techniques to reveal metal distribution within plaques. However, the exact role of metals in Alzheimer’s disease is still not known, “which is why it is important to correlate metal concentration and distribution within plaques to alterations of important biochemical parameters, such as lipids and proteins” said Paterson, who assisted with the collection and analysis of X-ray fluorescence microscopy data (XFM).
The bright source of X-rays produced by the Australian synchrotron is a major advantage for XFM.
“You have a high energy X-ray coming in and if it is absorbed by an iron atom it will re-emit X-rays at a very specific energy and we have detectors that can tell the difference between the X-rays coming from iron or copper. The more iron atoms there are in a particular location, the more fluorescence we will see from there,” said Paterson.
Not only can XFM differentiate between different elements, but X-ray fluorescence microscopy is a direct imaging technique that does not involve any staining. This is really important, as the typical staining methods often used to study Alzheimer’s disease, may remove important chemical information from the tissue.
“To be able to study metal and molecule distribution, without staining, is a really unique capability, and is made possible with synchrotron light” said Hackett.
The XFM beamline was used to complement Raman spectroscopy and infrared microspectroscopy in determining the location of specific metals within the plaque and classes of molecules such as lipids, cholesterol and aggregated protein. The results indicated that intense zinc and some iron were found within the plaque core, while the copper is spread out in a cloud-like shape at the periphery.”
“Because you can overlay the fluorescence images of each element, you acquire a useful chemical composite of the plaque,” said Paterson.
Supporting the XFM data, infrared imaging and Raman microscopy provided crucial information about the molecular structure within the plaques, in this case, the presence and amount of lipids. Surprisingly, while aggregated proteins were found to localise with Zn and Fe in the plaque core, lipids were found to localise with Cu at the plaque periphery.
“At this stage, we are unsure of the exact meaning of the co-localisation of lipids and Cu in the plaque core, however, we now have an imaging methodology that allows us to study this in the future, which is an important step forwards”, said Hackett.
“The IR microspectroscopy, when complemented by Raman microspectroscopy indicated that there was an increase in the levels of copper and lipids at the periphery of the plaque,” said instrument scientist Dr Mark Tobin, who assisted in the data collection and analysis of the Synchrotron source FTIR.
“Future research into the interactions between copper and the lipids in the amyloid plaque is worthy of further investigation.” said Hackett.
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Approximately 190 participants attended the first combined ANSTO User Meeting, which was held at the Australian Synchrotron 22-24 November.
The event brought representatives of research communities together who have accessed various ANSTO infrastructure platforms.
“It was an opportunity to look at the scientific challenges and questions that are being addressed and consider how multiple techniques and experimental methods can be applied to answering those questions,” said co-convenor Dr Miles Apperley, Head of Research Infrastructure, who spoke at the opening.
ANSTO has nine research infrastructure platforms in total, including the Australian Centre for Neutron Scattering and the Australian Synchrotron that provide user-focused open-access support to researchers from Australia and across the globe.
Plenary speakers included leading Australian and International researchers.
Dr Michael Drakopoulos reviewed the basics of using the I12 beamline at the Diamond Light Source in the UK.
Professor Ian Gentle Deputy Executive Dean and Associate Dean Research of the Faculty of Science at the University of Queensland spoke about the use of neutrons to understand diffusion and stability of materials in organic optoelectronic devices.
Professor Elena P. Ivanova, a nano/biotechnology expert from the University of Swinburne, shared her research deciphering the enigma of bactericidal pattern of insect wing epicuticle.
Associate Professor Rachel Popelka-Filcoff of Flinders University shared how Indigenous Australian natural pigments can be explored using nuclear and spectroscopic methods.
Professor Sharon Robinson, Associate Dean Graduate Research and a Senior Professor in Biological Sciences discussed species on the move in Antarctic Terrestrial Communities.
The speakers emphasised emerging science trends in their respective fields and how new technologies and capabilities benefit that research.
Both ANSTO and researchers from other Australian institutions contributed to sessions over the three days.
ANSTO scientists described the capabilities that support their own research outcomes as they develop and apply leading edge instrument methods and techniques.
They included include Tom Carodoc- Davies, Gabriel Murphy, Jason Price, Kathleen Wood, Katie Sizeland, Pimm Vongsvivut, Wai Tung Lee, Mark Tobin, Vladimir Levchenko,
Anna Sokolova, Cameron Kewish, Anton Stampfl, Daniele Hausermann, Susan Cumberland, Santosh Panjikar, Michael Hotchkis, Jun Aishima, Peter Kappen, Dehong Yu, Stephen Holt, Ulf Garbe, Garry McIntyre, Zeljko Pastuovic, Mark Reid, and Zhiyang Wang.
Prof Michael James outlined the new BRIGHT Beamlines that are planned for the Australian Synchrotron.
Prof Andrew Peele awarded the Stephen Wilkins Medal to Leonie van ‘t Hag for her PhD thesis on the application of a crystallographic technique that is used to crate 3d structures of proteins.
“It is not just stainless steel and digital systems that make up the infrastructure which our users encounter at our facilities, but the expertise and dedication of our staff who ensure that they can turn that information into knowledge and innovation,“ said Apperley.
The organising committee was chaired by Dr Anthony Chesman from CSIRO, who is a user of the Australian Synchrotron, and comprised representatives of the ANBUG and Synchrotron user communities and ANSTO platforms.
The combined Users Meeting will be held in the multi-disciplinary format every second year and revert to separate user community meetings on the alternate years to ensure important focused and discipline specific work can continue.