New research helps pursuit for malaria vaccine

Scientists from The Hospital for Sick Children (SickKids) identify structure of key malaria protein

Using technology available at the Canadian Light Source synchrotron, SickKids scientists have taken an important step forward on the path to finding effective biomedical interventions to halt the spread of malaria, a disease that affected an estimated 216 million people worldwide in 2016 alone.

Jean-Philippe Julien, a scientist in the Molecular Medicine program at SickKids, and his colleagues focused on a molecule known to be essential for the malaria parasite Plasmodium falciparum to go through the sexual stages of its lifecycle. Disrupting that stage of the lifecycle has the potential to reduce infections and deaths from malaria because parasite transmission between humans would be blocked by inhibiting parasite development in the Anopheles mosquito.

“The protein we looked at was identified several years ago as an important target for malaria parasite biology,” says Julien, who is also a Canada Research Chair in Structural Immunology and an Assistant Professor in the Departments of Biochemistry and Immunology at the University of Toronto. “The field has tried for over a decade to clarify its structure in order to guide the development of biomedical interventions that can curb the spread of malaria.”

>Read more on the Canadian Light Source website

Image: One of the structures of the malaria protein (orange) being recognized by the humanized blocking antibody (green and blue).

Structures reveal new target for malaria vaccine

The discovery paves the way for the development of a more effective and practical human vaccine for malaria, a disease responsible for half a million deaths worldwide each year.

Malaria kills about 445,000 people a year, mostly young children in sub-Saharan Africa, and sickens more than 200 million. It’s caused by a parasite, Plasmodium falciparum (Pf), and is spread to humans through the bite of an infected Anopheles mosquito.

The parasite’s complex life cycle and rapid mutations have long challenged vaccine developers. Only one experimental vaccine, known as RTS,S, has progressed to a Phase 3 clinical trial (testing on large groups of people for efficacy and safety). To elicit an immune response, this vaccine uses a fragment of circumsporozoite protein (CSP), which covers the malaria parasite in its native conformation. However, the trial results showed that RTS,S is only moderately effective, protecting about one-third of the young children who received it over a period of four years.

>Read more on the Advanced Light Source website.

Image (a) Left: Surface representation of CIS43 (light chain in tan and heavy chain in light blue), with peptide 21 shown as sticks (purple). Right: A 90° rotation of the representation. See entire image here.

Fighting malaria with X-rays

Today 25 April, is World Malaria Day.

Considered as one of humanity’s oldest life-threatening diseases, nearly half the world population is at risk, with 216 million people affected in 91 countries worldwide in 2016. Malaria causes 445 000 deaths every year, mainly among children. The ESRF has been involved in research into Malaria since 2005, with different techniques being used in the quest to find ways to prevent or cure the disease.

Malaria in humans is caused by Plasmodium parasites, the greatest threat coming from two species: P. falciparum and P. vivax. The parasites are introduced through the bites of infected female Anopheles mosquitoes. They travel to the liver where they multiply, producing thousands of new parasites. These enter the blood stream and invade red blood cells, where they feed on hemoglobin (Hgb) in order to grow and multiply. After creating up to 20 new parasites, the red blood cells burst, releasing daughter parasites ready for new invasions. This life cycle leads to an exponential growth of infected red blood cells that may cause the death of the human host.

The research carried out over the years at the ESRF has aimed to identify mechanisms critical for the parasite’s survival in the hope of providing an intelligent basis for the development of drugs to stop the parasite’s multiplication and spread.

>Read more on the European Synchrotron website

Image: Inside the experimental hutch of the ESRF’s ID16A nano-analysis beamlin.
Credit: Pierre Jayet

Hijacker parasite blocked from infiltrating blood

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.

>Read more on the Australian Synchrotron website

 

Malaria in Action

Seeing the invisible

In 2007 Helen Saibil was at a conference in Australia. Amongst the presentations there happened to be talks on the parasites malaria and toxoplasma and how they infect mammalian cells, causing disease. Helen is a structural biologist and whilst listening she began to realise that her newly acquired skills -she was doing electron tomography of cells- might allow the researchers to see things they had never seen before.

Electron tomography reveals structures in the interiors of cells in great detail. What she hoped was that it could be used to look at the malaria parasites inside red blood cells [See images below] to get a better understanding of what they do there. Helen approached one of the speakers, Mike Blackman, then at the National Institute for Medical Research at Mill Hill in London, and so began a thriving collaboration. One that has produced the remarkable pictures of malaria parasites breaking out of infected human red blood cells on this page.

Helen Saibil and her colleagues used electron tomography to peer into malaria infected cells, looking at the parasites hiding and multiplying inside. The technique produces exquisitely detailed pictures able to reveal very tiny features, but it has one big drawback. Electrons cannot penetrate deep into the sample so it only works on very thinly sliced samples, much thinner than an individual cell. As a result it cannot be used to look at entire cells, or in this case red blood cells containing malaria parasites.

>Read more on the Diamond Light Source website

 

Crystallographers identify 1,000 protein structures

The Canadian Light Source is celebrating two milestones reached by scientists who have conducted research at the national facility at the University of Saskatchewan.

Scientists have solved 1,000 protein structures using data collected at CLS’s CMCF beamlines. These have been added to the Protein Data Bank – a collection of structures solved by researchers globally. Researchers have also published 500 scientific papers based on their work using the crystallography beamlines.

Proteins are the building blocks of life and are described as the body’s workhorses. The body is made of trillions of cells. Cells produce proteins, which do the work of breaking down food, sending messages to other cells, and fighting bacteria, viruses and parasites. The discoveries at the CLS range from how the malaria parasite invades red blood cells to why superbugs are resistant to certain antibiotics and how parkin protein mutations result in some types of Parkinson’s disease. Understanding how these and other such proteins work can potentially save millions of lives.

>Read more on the Canadian Light Source website

Image: PDB ID: 6B0S

 

New insights about malaria parasites infection mechanisms

Unraveled details about how the malaria parasite acts after invading the red blood cells.

This highlight has been possible thanks to two advanced microscope techniques combination: X-ray fluorescence microscopy and soft X-rays tomography, this one conducted in ALBA Synchrotron. Infected red blood cells image analysis offer new information that could yield new drugs design against malaria, an illness that claims over 400.000 lives each year.
Plasmodium falciparum causes the malaria disease. This parasite, transmitted through mosquito sting, infects red blood cells of its victim. Once inside, it uses hemoglobin (the protein in charge of oxygen transport) as a nutrient. When it is digested, iron is released in a form of heme molecules. These heme molecules are toxic to the parasite, but it has a strategy to make them harmless: it packs heme in pairs and finally they are packed forming hemozoin crystals. In this way, poisonous iron is locked up and no longer will be a threat for the parasite.


>Read More on the ALBA website

Infographic: Model for biochemistry processes that occur inside the parasite. The parasite takes the hemoglobin from the red blood cell (RBC)
1 and digests it inside the digestive vacuole (DV)
2. as a consequence, heme groups are released
3. and HDP protein packages them in pairs (heme dimers)
4. finally, in the crystallization process these dimers are converted in hemozoin crystals
5. blue arrow points out the suggested feedback mechanism that regulates hemoglobin degradation.