Viral and parasitic diseases are not only worth killing off, they are also increasingly vulnerable

 

Oct 10th 2015 | From the print edition TO EXTERMINATE a living species by accident is normally frowned on. To do so deliberately might thus seem an extraordinary sin. But if that species isPlasmodium falciparum, the sin may be excused. This parasitic organism causes the most deadly form of malaria. Together with four cousins, it is responsible for about 450,000 deaths a year, and the ruination of the lives of millions more people who survive the initial crisis of disease. Besides the direct suffering this causes, the lost human potential is enormous. The Gates Foundation, an American charity, reckons that eradicating malaria would bring the world $2 trillion of benefits by 2040.   Malaria is one of the worst examples of the damage that transmissible diseases can wreak. But it is not alone. AIDS carries off fit, young adults by the millions and tuberculosis by the hundreds of thousands. Measles, whooping cough and diarrhoea together kill over 1m children a year. Parasitic worms and mosquito-borne viruses like dengue, though they take relatively few lives, debilitate many. Campaigns have brought the toll down heroically. As recently as 2000, malaria killed around 850,000 people a year; likewise, since 2000 deaths from measles have fallen by 75%, to around 150,000. These successes are to be celebrated, but an even greater prize exists: to go beyond controlling infections and infestations and instead to eradicate some of them completely, by exterminating the pathogens and parasites that cause them. That has been accomplished a couple of times in the past, for smallpox (a human disease) and rinderpest (a cattle disease similar to measles). The end is reckoned to be close for polio (a virus that once killed and crippled millions) and dracunculiasis (a parasitic worm). But more must follow. Swat teams Some diseases are not suitable for eradication because the organisms that cause them hang around in the environment, or have other animal hosts. Others, such as tuberculosis, can infect people “silently”, without causing symptoms, so are invisible to doctors. But sometimes the culprit is a poverty of ambition. A list of five plausible targets—measles, mumps, rubella, filariasis and pork tapeworm—has hardly changed since the early 1990s, yet measles, mumps and rubella are all the subjects of intensive vaccination campaigns that could easily be converted into ones of eradication. And even though Swaziland is poised to become the first malaria-free country in sub-Saharan Africa (see article), only a few dare to make explicit the goal of ridding the planet of the disease. Hepatitis C should be made a target, too. It kills half a million a year, and affects rich and poor countries alike, yet new drugs against it are almost 100% effective and there are no silent carriers. Eradicating these seven diseases—the five, plus malaria and hepatitis C—would save a yearly total of 1.2m lives. It would transform countless more. People argue that the cost of chasing down the last few cases of a disease is not worth it. If the mass-vaccination campaigns under way can lower the incidence of measles, mumps, rubella and so on in poor countries to something close to rich-world levels, the argument goes, that is surely good enough. Well, it isn’t. A disease can bounce back. That is what malaria did in the 1960s, when political attention waned, and the parasites that cause it evolved resistance to drugs and the mosquitoes that spread it evolved resistance to insecticides. Three big improvements underpin the argument for throwing eradication’s net more widely. The first is better communications. The technology for locating and monitoring cases of disease in poor countries, even when few and far between, has improved immeasurably in the past two decades with the spread of mobile phones and the internet, and the expansion of road networks. The second is better medical technology. The reason filariasis is on the “possibles” list, for example, is the invention of ivermectin, a drug that kills the worm which causes it. The inventors of this drug won half of this year’s Nobel prize for medicine (see article). The other half was won by the woman who came up with an answer to drug resistance in malaria—a medicine called artemisinin, which has been crucial to the success of the recent push against the disease. (This time, alert to the risk of resistance, doctors have formulated it with other drugs to create combination therapies that natural selection finds hard to get around.) Even better technology is in the pipeline. In the case of mosquito-borne illnesses such as malaria and dengue, genetic engineering promises ways of making the insects resistant to the pathogens that they pass on to people, of crashing the mosquito population, and even of attacking insects and pathogens with genetically modified fungi and bacteria. Genetic engineering also promises a wide range of new vaccines. The third reason for seeking eradication is a change in political attitudes. The emergence of AIDS, in particular, made governments everywhere sit up and take notice. Last year’s west African outbreak of Ebola only reinforced the message. Political attention leads to better medical infrastructure. To deal with AIDS, new networks of clinics were created and staffed with trained personnel. These can serve as the backbone of the campaigns that would be the starting-point for many extermination programmes. The Dalek doctrine The list of candidates for such programmes should be extended as and when circumstances change. The biggest prize might be AIDS itself. Smallpox, the first target for eradication, was picked in part because the virus that caused it had only humans as hosts and could not survive independently for more than a few hours. It had, in other words, no hiding place. Both of these are true of HIV, the AIDS-causing virus. What is missing is the third ingredient for smallpox: a reliable vaccine. Throughout history, humans and disease have waged a deadly and never-ending war. Today the casualties are chiefly the world’s poorest people. But victory against some of the worst killers is at last within grasp. Seize it. From the print edition: Leaders   http://www.economist.com/news/leaders/21672213-viral-and-parasitic-diseases-are-not-only-worth-killing-they-are-also-increasingly?fsrc=scn%2Fesp%2FFB

Researchers identify new target for malaria treatment

 

The breakthrough, which focuses on a membrane separating parasites from their host cells, was made when studying Toxoplasma gondii (pictured) (Credit: Centers for Disease Control and Prevention) A team of MIT researchers has discovered a new target for drug treatments for prevalent diseases such as malaria. The findings focus on a membrane between the parasite and its host cell, with scientists successfully identifying a family of proteins that, when targeted, could cut off nutrients to the parasite. Many diseases, such as malaria and tuberculosis, are caused by pathogens that exist in separate compartments within their host cells, known as parasitophorous vacuoles. The vacuole is separated from the host cytoplasm by a membrane, which protects the disease from the cell's defences. However, it also makes it difficult for the pathogen to access vital nutrients, and release the proteins necessary to spread the disease. This means that the parasite has to develop a way to get around its own barrier in order to access nutrients essential to its survival. Previous studies have revealed that the membrane is selectively permeable, but scientists have been unable to determine the molecular makeup of the pores. The MIT researchers were studying Toxoplasma, investigating how the parasite is able to release its proteins into the host cell and beyond, when they stumbled upon a discovery. They found that two proteins – GRA17 and GRA23 – were central to the process, and were of shared ancestry to proteins in the parasite Plasmodium, which were themselves responsible for a protein export system within their host cell. However, when the team stopped the proteins from functioning, the export process of parasite proteins beyond the vacuole was unchanged. Puzzled by the specific role of the proteins in the export process, the researchers added dyes to the host cell and disabled the proteins once more. Observing the cells again, they found that the proteins were no longer able to flow through the selective membrane and into the vacuole, strongly indicating that GRA17 and GRA23 are responsible for the small-molecule transfer between the host cell and the parasitophorous vacuole. Furthermore, when the team switched the export protein from the Plasmodium parasite into the Toxoplasma, the dyes were able to flow into the vacuole once more, suggesting that the family of proteins responsible for the process had indeed been successfully identified. "This very strongly suggests that you could find small-molecule drugs to target these pores, which would be very damaging to these parasites, but likely wouldn’t have any interaction with any human molecules," says research lead Dan Gold. "So I think this is a really strong potential drug target for restricting the access of these parasites to a set of nutrients." The findings were recently published in journal Cell & Microbe. Source: MIT

Promising compound rapidly eliminates malaria parasite

 

A new report says that the rapid action of (+)-SJ733 will likely slow malaria drug resistance. An international research collaborative has determined that a promising anti-malarial compound tricks the immune system to rapidly destroy red blood cells infected with the malaria parasite but leave healthy cells unharmed. St. Jude Children's Research Hospital scientists led the study, which appears in the current online early edition of the Proceedings of the National Academy of Sciences (PNAS). The compound, (+)-SJ733, was developed from a molecule identified in a previous St. Jude-led study that helped to jumpstart worldwide anti-malarial drug development efforts. Malaria is caused by a parasite spread through the bite of an infected mosquito. The disease remains a major health threat to more than half the world's population, particularly children. The World Health Organization estimates that in Africa a child dies of malaria every minute. In this study, researchers determined that (+)-SJ733 uses a novel mechanism to kill the parasite by recruiting the immune system to eliminate malaria-infected red blood cells. In a mouse model of malaria, a single dose of (+)-SJ733 killed 80 percent of malaria parasites within 24 hours. After 48 hours the parasite was undetectable. Planning has begun for safety trials of the compound in healthy adults. Laboratory evidence suggests that the compound's speed and mode of action work together to slow and suppress development of drug-resistant parasites. Drug resistance has long undermined efforts to treat and block malaria transmission. "Our goal is to develop an affordable, fast-acting combination therapy that cures malaria with a single dose," said corresponding author R. Kiplin Guy, Ph.D., chair of the St. Jude Department of Chemical Biology and Therapeutics. "These results indicate that SJ733 and other compounds that act in a similar fashion are highly attractive additions to the global malaria eradication campaign, which would mean so much for the world's children, who are central to the mission of St. Jude." Whole genome sequencing of the Plasmodium falciparum, the deadliest of the malaria parasites, revealed that (+)-SJ733 disrupted activity of the ATP4 protein in the parasites. The protein functions as a pump that the parasites depend on to maintain the proper sodium balance by removing excess sodium. The sequencing effort was led by co-author Joseph DeRisi, Ph.D., a Howard Hughes Medical Institute investigator and chair of the University of California, San Francisco Department of Biochemistry and Biophysics. Investigators used the laboratory technique to determine the makeup of the DNA molecule in different strains of the malaria parasite. Researchers showed that inhibiting ATP4 triggered a series of changes in malaria-infected red blood cells that marked them for destruction by the immune system. The infected cells changed shape and shrank in size. They also became more rigid and exhibited other alterations typical of aging red blood cells. The immune system responded using the same mechanism the body relies on to rid itself of aging red blood cells. Another promising class of antimalarial compounds triggered the same changes in red blood cells infected with the malaria parasite, researchers reported. The drugs, called spiroindolones, also target the ATP4 protein. The drugs include NITD246, which is already in clinical trials for treatment of malaria. Those trials involve investigators at other institutions. "The data suggest that compounds targeting ATP4 induce physical changes in the infected red blood cells that allow the immune system or erythrocyte quality control mechanisms to recognize and rapidly eliminate infected cells," DeRisi said. "This rapid clearance response depends on the presence of both the parasite and the investigational drug. That is important because it leaves uninfected red blood cells, also known as erythrocytes, unharmed." Laboratory evidence also suggests that the mechanism will slow and suppress development of drug-resistant strains of the parasite, researchers said. Planning has begun to move (+)-SJ733 from the laboratory into the clinic beginning with a safety study of the drug in healthy adults. The drug development effort is being led by a consortium that includes scientists at St. Jude, the Swiss-based non-profit Medicines for Malaria Venture and Eisai Co., a Japanese pharmaceutical company. Story Source: The above story is based on materials provided by St. Jude Children's Research Hospital. Note: Materials may be edited for content and length. Journal Reference: María Belén Jiménez-Díaz, Daniel Ebert, Yandira Salinas, Anupam Pradhan, Adele M. Lehane, Marie-Eve Myrand-Lapierre, Kathleen G. O’Loughlin, David M. Shackleford, Mariana Justino de Almeida, Angela K. Carrillo, Julie A. Clark, Adelaide S. M. Dennis, Jonathon Diep, Xiaoyan Deng, Sandra Duffy, Aaron N. Endsley, Greg Fedewa, W. Armand Guiguemde, María G. Gómez, Gloria Holbrook, Jeremy Horst, Charles C. Kim, Jian Liu, Marcus C. S. Lee, Amy Matheny, María Santos Martínez, Gregory Miller, Ane Rodríguez-Alejandre, Laura Sanz, Martina Sigal, Natalie J. Spillman, Philip D. Stein, Zheng Wang, Fangyi Zhu, David Waterson, Spencer Knapp, Anang Shelat, Vicky M. Avery, David A. Fidock, Francisco-Javier Gamo, Susan A. Charman, Jon C. Mirsalis, Hongshen Ma, Santiago Ferrer, Kiaran Kirk, Iñigo Angulo-Barturen, Dennis E. Kyle, Joseph L. DeRisi, David M. Floyd, R. Kiplin Guy. ( )-SJ733, a clinical candidate for malaria that acts through ATP4 to induce rapid host-mediated clearance ofPlasmodium. Proceedings of the National Academy of Sciences, 2014; 201414221 DOI: 10.1073/pnas.1414221111

New molecules to burst malaria's bubble

 

December 3, 2014 Australian National University Scientists have released details of a raft of new chemicals with potent anti-malarial properties which could open the way to new drugs to fight malaria. Over 200 million people contract malaria each year, and the parasite that causes the disease has become resistant to most of the drugs currently available. The papers show the malaria parasite has real Achilles heel, and we now have range of new ways to attack it. Dr Natalie Spillman. Scientists have released details of a raft of new chemicals with potent anti-malarial properties which could open the way to new drugs to fight the disease. A new paper in PNAS is the third published recently by a group at the Australian National University (ANU). The group has collaborated with scientists from around the globe to uncover potential ammunition in the fight against malaria. Over 200 million people contract malaria each year, and the parasite that causes the disease has become resistant to most of the drugs currently available. "The series of papers shows that the malaria parasite has a real Achilles heel, and describe a range of new ways to attack it," said Professor Kiaran Kirk, Dean of the College of Medicine, Biology and Environment and one of the scientists involved in the project. Dr Natalie Spillman, from the Research School of Biology at ANU studied the mechanism by which the parasites are killed. "The new molecules block a molecular salt pump at the surface of the parasite, causing it to fill up with salt," Dr Spillman said "This has the effect of drawing water into the parasite, causing it to swell uncontrollably and burst." Although the process of developing the new compounds into clinical drugs is complex and lengthy, Professor Kirk is optimistic the findings will lead to new treatments. "It's very early days, but these pump-blocking compounds have some of the most promising anti-malarial potential we've seen," he says. Aspects of the work were carried out with groups at Griffith University, Monash University and the Menzies School of Health Research in Darwin. "This is a good example of a long-term, international drug development program in which Australian groups have played a key role," he said. Story Source: The above story is based on materials provided by Australian National University. Note: Materials may be edited for content and length. Journal Reference: María Belén Jiménez-Díaz, Daniel Ebert, Yandira Salinas, Anupam Pradhan, Adele M. Lehane, Marie-Eve Myrand-Lapierre, Kathleen G. O’Loughlin, David M. Shackleford, Mariana Justino de Almeida, Angela K. Carrillo, Julie A. Clark, Adelaide S. M. Dennis, Jonathon Diep, Xiaoyan Deng, Sandra Duffy, Aaron N. Endsley, Greg Fedewa, W. Armand Guiguemde, María G. Gómez, Gloria Holbrook, Jeremy Horst, Charles C. Kim, Jian Liu, Marcus C. S. Lee, Amy Matheny, María Santos Martínez, Gregory Miller, Ane Rodríguez-Alejandre, Laura Sanz, Martina Sigal, Natalie J. Spillman, Philip D. Stein, Zheng Wang, Fangyi Zhu, David Waterson, Spencer Knapp, Anang Shelat, Vicky M. Avery, David A. Fidock, Francisco-Javier Gamo, Susan A. Charman, Jon C. Mirsalis, Hongshen Ma, Santiago Ferrer, Kiaran Kirk, Iñigo Angulo-Barturen, Dennis E. Kyle, Joseph L. DeRisi, David M. Floyd, R. Kiplin Guy. ( )-SJ733, a clinical candidate for malaria that acts through ATP4 to induce rapid host-mediated clearance ofPlasmodium. Proceedings of the National Academy of Sciences, 2014; 201414221 DOI: 10.1073/pnas.1414221111

Why humans don't suffer from chimpanzee malaria: DNA region controlling red blood cell invasion holds genetic key to infection

 

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A chimpanzee in Koulamoutou, Ogooué-Lolo Province, Gabon.

The DNA region controlling red-blood-cell invasion holds the genetic key to human malaria infection, according to new research.

By comparing the genomes of malaria parasites that affect chimpanzees and those that affect humans, researchers discovered that it is the difference in the parasites' surface proteins that determine which host it will infect.

A genetic region responsible for red blood cell invasion was among a small number of areas found to differ between the genomes of malaria parasites that affect chimpanzees and Plasmodium falciparum, the parasite responsible for the deaths of more than half a million children each year.

Out of a genome of approximately 5,500 genes, researchers found that most genes have directly equivalent counterparts between the human and primate parasites. However, portions of the P. falciparum genome that differed most profoundly from the P. reichenowi parasite that infects chimpanzees were found to encode proteins that help the parasite to bind to and invade red blood cells, which is where the parasite grows and multiplies.

"Discovering that the key differences lie in genes responsible for red blood cell invasion reassures us that we've been looking in the right place," says Dr Thomas Otto, first author at the Wellcome Trust Sanger Institute. "Researchers have identified surface proteins as promising vaccine candidates already; and our finding adds more support, showing that it is the difference in the parasites' surface proteins that determine which host it will infect."

This is the first time that an essentially complete genome has been produced for a malaria parasite that infects such a close relative of humans. It provides the first systematic view of the differences between parasites that infect humans and those that infect our close relatives. Human malaria emerged from the Great Apes, so this comparison using chimpanzee malaria is the closest that scientists have come to a full catalogue of the changes associated with parasites switching from our primate relatives into humans.

Plasmodium parasites export proteins to the surface of red blood cells, allowing infected red blood cells to stick to the wall of blood vessels. In human malaria, the best characterised of these proteins are encoded by a highly variable family of genes, allowing the parasites to evade the host immune response and continue the infection. Surprisingly basic rules about this gene family are preserved between chimpanzee and human malaria: despite huge variation in the individual sequence of these surface antigen genes, their absolute numbers and the numbers of sub-types are remarkably preserved. By contrast, other surface antigen repertoires differed very significantly in their numbers.

"Since P. reichenowi and P. falciparum split apart, the major surface antigen gene family has not expanded or contracted; it's locked at some kind of optimised level," says Dr Matt Berriman, senior author at the Sanger Institute.

DNA used for this research was obtained by the Centre for Disease Control from a chimpanzee infected with a strain of P. reichenowi isolated in the 1950s. This chimpanzee was subsequently cured of the malaria infection. Additional blood samples were collected from orphaned infant chimpanzees infected in the wild with a similar parasite called P. gaboni. The samples were obtained from chimpanzees undergoing routine health checks at a primate sanctuary in Gabon, West Africa.

Malaria: Blood cells behaving badly

 

June 10, 2014

American Institute of Physics (AIP)

New insight into how malaria parasites perturb flow, turning infected cells into sticky capillary cloggers, may lead to new and better treatments. All the billions of flat, biconcave disks in our body known as red blood cells (or erythrocytes) make three basic, tumbling-treadmill-type motions when they wend their way through the body's bloodstream ferrying oxygen from our lungs to our brains and other tissues. That is, unless they are infected with malaria parasites, in which case their motions are completely different.

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New insight into how malaria parasites perturb flow, turning infected cells into sticky capillary cloggers, may lead to new and better treatments.

A team of researchers at the National University of Singapore (NUS) has discovered this striking difference by comparing the flow dynamics of healthy vs. malaria-infected red blood cells. Reported this week in the Journal of Applied Physics, from AIP Publishing, their work may provide insights into developing better-targeted drug treatments for malaria in the future.

"By gaining a better understanding of why and how erythrocytes undergo changes in geometry and physical properties, we hope to elucidate such changes as possible targets for possible effective treatment of malaria," said Nhan Phan-Thien, a professor in the Department of Mechanical Engineering at the National University of Singapore.

Malaria, a life-threatening disease caused by Plasmodium parasites, afflicts hundreds of millions of people each year and is responsible for more than half a million deaths -- mostly children living in Sub-Saharan Africa. Transmitted through the saliva of a female Anopheles mosquito, the parasites have a complicated, multi-stage life cycle part of which is spent inside the red blood cells of their human host.

Once the mosquito takes a blood meal and infects a person, malaria parasites invade red blood cells, making the cells stiffer and stickier. These cells also morph from a bi-concave shape to a more spherical form during the late "schizont stage" of malaria, which occurs 36 to 48 hours after onset of the infection. When red blood cells become stiff and deformed, they can become stuck in narrow capillaries and cause anemia, because fewer blood cells can flow to deliver oxygen to the different organs in the body, including the brain.

In the new paper, the NUS team reports how they used a particle-based method called "dissipative particle dynamics" to zero in on the three typical modes of motion of a cell or capsule in shear flow -- tank-treading, tumbling, or trembling -- and uncover the behavior of healthy and malaria-infected erythrocytes.

"Tank-treading mode is a steady state, in which a cell remains stationary while its membrane rotates around the internal fluid continuously," Phan-Thien explained. "Tumbling mode is an unsteady state in which the cell flips or tumbles periodically in its original shape as a rigid body. And the trembling mode is a transitional state between the two other modes, and is characterized by a shape variation and an angular oscillation."

The team discovered that, when experiencing the same shear rate, if a healthy erythrocyte undergoes a tumbling motion, the malaria-infected cell instead exhibits only a tumbling motion.

What advantage can malaria parasites gain by affecting the tumbling motion of erythrocytes? "Tumbling may allow the red blood cell to make better contact with the blood vessel wall and provide an opportunity to adhere to it," said Phan-Thien. The advantage to the parasite in making the red blood cell stick could be that it stalls the cells and keeps them from circulating and be cleared by the spleen or the immune system.

The researchers also found that at rates where a healthy erythrocyte undergoes a trembling motion, a malaria-infected cell can't exhibit the tank-treading motion. "And if a healthy erythrocyte undergoes a tank-treading motion, the malaria-infected one will exhibit any one of the three dynamic motions," noted Phan-Thien.