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New hope for fighting malaria: Decoding human antibodies

2023/11/232023/11/30

Using CMCF beamline, researchers from Hospital for Sick Children decode how human antibodies protect us against malaria

Researchers from The Hospital for Sick Children (SickKids) recently decoded how human antibodies protect us from the malaria parasite, which kills more than 600,000 people worldwide annually. The CMCF facility at the Canadian Light Source at the University of Saskatchewan helped them identify the precise structures involved in identifying and fighting off the disease.

“The key question that we hoped to address was what made a protective antibody protect? What makes it tick, what makes it better than some that might not be so protective and might not be so potent?” says SickKids researcher Elaine Thai.

They were able to see that protective antibodies lock on to a vulnerable point on the malaria parasite in a specific form, making it easier to neutralize the infection.

The results, published in Cell Reports, point to a way forward to better treatments and vaccines.

While there are two vaccines approved today, they can only be used on the very young, have limited protective power, and the effects fade over time. Researchers can take the maps created by projects like this to engineer better tools for healthcare.

Read more on Canadian Light Source website

New hope in the fight against malaria

2023/06/132023/06/14

Scientists have identified and characterized a new inhibitor that prevents the malaria parasite to infect human red blood cells. It is non-toxic to human cells and targets a nanomotor of the parasite. Structural studies conducted at the ESRF beamlines, in collaboration with teams from the Curie Institute and Vermont University, elucidate the novel mode of inhibition that paves the way for new preventative medications against this disease. The results are published today in Nature Communications.

Malaria infection in humans, caused by the Plasmodium parasites and transmitted via the bite of an infected Anopheles mosquito, is a prominent global health issue. In 2020, malaria caused 627,000 deaths, the majority being children under the age of five according to the WHO. In 2021, nearly half of the world’s population was at risk of malaria. The European Centre for Disease Prevention and Control states that with global climate change, there is a risk that malaria appears in Europe in the coming decades.

In recent years, there has been a remarkable progress in antimalarial therapeutics. However, the parasite is developing resistance to all existing treatments, including current first-line treatments containing artemisinin-based therapies. The first ever malaria vaccine is on the market since October 2021, however its efficacy is relatively modest.

Therefore, the international community is still on the lookout for novel treatments. Six years ago, an international collaboration of scientists, including the Institut Curie in France (Julien Robert-Paganin & Anne Houdusse), the University of Vermont in the USA (Kathleen Trybus) and Imperial College in the United Kingdom (Jake Baum) investigated a large molecular complex called the glideosome that plays a crucial role in the movement of the Plasmodium falciparum (Pf) parasite.

Read more on the ESRF website

Image: Dihia Moussaoui, co-first author of the paper and post-doctoral researcher at the ESRF, during the experiments at the structural beamline ID30B at the ESRF, the European Synchrotron

Credit: ESRF

How deadly parasites ‘glide’ into human cells

2020/10/262020/10/29

X-ray analysis reveals structure of molecular machinery of malaria and toxoplasmosis pathogens

An investigation at DESY’s X-ray source PETRA III provides new insights into the molecular machinery by which certain parasites travel through the human organism. The study, led by Christian Löw from the Hamburg branch of the European Molecular Biology Laboratory EMBL, analyzed the so-called gliding movement of the malaria and toxoplasmosis parasites. The results, which the interdisciplinary team presents in the journal Communications Biology, can aid the search for new drugs against the pathogens.

In biological terms, gliding refers to the type of movement during which a cell moves along a surface without changing its shape. This form of movement is unique to parasites from the phylum Apicomplexa, such as Plasmodium and Toxoplasma. Both parasites, which are transmitted by mosquitoes and cats, have an enormous impact on global heath. Plasmodium causes 228 million malaria infections and around 400 000 deaths per year. Toxoplasma, which infects even one third of the human population, can cause severe symptoms in some people, and is particularly dangerous during pregnancy.

Read more on the DESY PETRA III website

Image: Molecular structure of essential light chain (ELC) protein in Plasmodium glideosome. Blue represents the electron density of the protein, with bonds between atoms indicated in yellow and water molecules indicated in red. The crystal structure at a resolution of 1.5 Ångström (0.15 millionths of a millimetre) was obtained at the EMBL beamlines at DESY’S X-ray source PETRA III. Credit: EMBL, Samuel Pazicky

The mechanism of the most commonly used antimalarial drugs unveiled

2019/10/282019/11/01

For centuries, quinoline has been an effective compound in antimalarial drugs, although no one knew its mode of action in vivo.

Today, a team led by the Weizmann Institute has discovered its mechanism in infected red blood cells in near-native conditions, by using the ESRF, Alba Synchrotron and BESSY. They publish their results in PNAS.

Malaria remains one of the biggest killers in low-income countries. Estimates of the number of deaths each year range from 450,000 to 720,000, with the majority of deaths happening in Africa. In the last two decades, the malaria parasite has evolved into drug-resistant strains. “Recently, the increasing geographical spread of the species, as well as resistant strains has concerned the scientific community, and in order to improve antimalarial drugs we need to know how they work precisely”, explains Sergey Kapishnikov, from the University of Copenhagen, in Denmark, and the Weizmann Institute, in Israel, and leader of the study.

Plasmodium parasite, when infecting a human, invades a red blood cell, where it ingests hemoglobin to grow and multiply. Hemoglobin releases then iron-containing heme molecules, which are toxic to the parasite. However, these molecules crystallise into hemozoin, a disposal product formed from the digestion of blood by the parasite that makes the molecules inert. For the parasite to survive, the rate at which the heme molecules are liberated must be slower or the same as the rate of hemozoin crystallization. Otherwise there would be an accumulation of the toxic heme within the parasite.

>Read more on the ESRF website

Image (taken from BESSY II article): The image shows details such as the vacuole of the parasites (colored in blue and green) inside an infected blood cell.
Credit: S. Kapishnikov

Two other institutes, BESSY II at HZB and ALBA Synchrotron, have participated in this research. Please find here their published articles:

> X-ray microscopy at BESSY II reveal how antimalaria-drugs might work

> The mechanism of the most commonly used antimlalarial drugs in near- native conditions unveiled

Killing two parasites with one stone

2019/05/152019/05/21

Each year Malaria affects 219 million people, causing almost half a million deaths. Crysptosporidiosis is the leading cause of diarrheal diseases in infants, leading to 200,000 deaths a year. An international team of scientists, led by researchers at the University of Dundee, have discovered a molecule which clears the parasites that cause these two illnesses. Their results are published in PNAS.

Malaria is a well-known disease caused by the parasites Plasmodium falciparum and Plamodium vivax and is the target of many available medications. However, the development of drug resistance has led the scientific community search for new therapeutic molecules which might provide for chemoprotection, prevention of transmission, and the treatment of relapsing malaria.
Like malaria, cryptosporidiosis is also a disease caused parasites, in this case Cryptosporidium hominis and Cryptosporidium parvum. Although it does not have the same ‘visibility as Malaria, Cryptosporidiosis is the leading cause worldwide of moderate-to-severe diarrheal diseases in infants and is estimated to lead to more than 200,000 deaths a year. The disease and is also associated with malnutrition, stunted growth, and cognitive-development problems in children. The currently approved drug, nitazoxanide, has poor efficacy, particularly in the case of immune-compromised patients and malnourished children, where there is no effective treatment.

>Read more on the ESRF website

Image: Binding modes of ligands bound to PfKRS1 and CpKRS. (A) PfKRS1:Lys:2 showing the binding mode of 2 (C atoms, gold) bound to the ATP site of PfKRS1 (PDB ID code 6AGT) superimposed upon PfKRS1:Lys:cladosporin (cladosporin C atoms, slate; PDB ID code 4PG3). (B) PfKRS1:5 showing binding mode of 5 bound to PfKRS1 (PDB ID code 6HCU). (See the full image: here)

New research helps pursuit for malaria vaccine

2018/11/212018/11/22

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.”

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

2018/07/202018/08/06

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.

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

2018/04/252018/04/25

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

2018/01/052018/04/25

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.

Malaria in Action

2017/12/202018/01/15

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.

New insights about malaria parasites infection mechanisms

2017/10/042017/10/26

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.