Biologists at the University of California, San Diego have succeeded in engineering algae to produce potential candidates for a vaccine that would prevent transmission of the parasite that causes malaria, an achievement that could pave the way for the development of an inexpensive way to protect billions of people from one of the world’s most prevalent and debilitating diseases. Initial proof-of-principle experiments suggest that such a vaccine could prevent malaria transmission.
(up) The edible algae Chlamydomonas, seen here at UC San Diego, can be grown in ponds anywhere in the world. (Credit: SD-CAB)
Malaria is a mosquito-borne disease caused by infection with protozoan parasites from the genus Plasmodium. It affects more than 225 million people worldwide in tropical and subtropical regions, resulting in fever, headaches and in severe cases coma and death. While a variety of often costly antimalarial medications are available to travelers in those regions to protect against infections, a vaccine offering a high level of protection from the disease does not yet exist.
The use of algae to produce malaria proteins that elicited antibodies against Plasmodium falciparum in laboratory mice and prevented malaria transmission was published May 16 in the online, open-access journal PLoS ONE. The development resulted from an unusual interdisciplinary collaboration between two groups of biologists at UC San Diego — one from the Division of Biological Sciences and San Diego Center for Algae Biotechnology, which had been engineering algae to produce bio-products and biofuels, and another from the Center for Tropical Medicine and Emerging Infectious Diseases in the School of Medicine that is working to develop ways to diagnose, prevent and treat malaria.
Part of the difficulty in creating a vaccine against malaria is that it requires a system that can produce complex, three-dimensional proteins that resemble those made by the parasite, thus eliciting antibodies that disrupt malaria transmission. Most vaccines created by engineered bacteria are relatively simple proteins that stimulate the body’s immune system to produce antibodies against bacterial invaders. More complex proteins can be produced, but this requires an expensive process using mammalian cell cultures, and the proteins those cells produce are coated with sugars due to a chemical process called glycosylation.
“Malaria is caused by a parasite that makes complex proteins, but for whatever reason this parasite doesn’t put sugars on those proteins,” said Stephen Mayfield, a professor of biology at UC San Diego who headed the research effort. “If you have a protein covered with sugars and you inject it into somebody as a vaccine, the tendency is to make antibodies against the sugars, not the amino acid backbone of the protein from the invading organism you want to inhibit. Researchers have made vaccines without these sugars in bacteria and then tried to refold them into the correct three-dimensional configuration, but that’s an expensive proposition and it doesn’t work very well.”
Instead, the biologists looked to produce their proteins with the help of an edible green alga, Chlamydomonas reinhardtii, used widely in research laboratories as a genetic model organism, much like the fruit fly Drosophila and the bacterium E. coli. Two years ago, a UC San Diego team of biologists headed by Mayfield, who is also the director of the San Diego Center for Algae Biotechnology, a research consortium seeking to develop transportation fuels from algae, published a landmark study demonstrating that many complex human therapeutic proteins, such as monoclonal antibodies and growth hormones, could be produced by Chlamydomonas.
That got James Gregory, a postdoctoral researcher in Mayfield’s laboratory, wondering if a complex protein to protect against the malarial parasite could also be produced by Chlamydomonas. Two billion people live in regions where malaria is present, making the delivery of a malarial vaccine a costly and logistically difficult proposition, especially when that vaccine is expensive to produce. So the UC San Diego biologists set out to determine if this alga, an organism that can produce complex proteins very cheaply, could produce malaria proteins that would inhibit infections from malaria.
“It’s too costly to vaccinate two billion people using current technologies,” explained Mayfield. “Realistically, the only way a malaria vaccine will ever be used is if it can be produced at a fraction of the cost of current vaccines. Algae have this potential because you can grow algae any place on the planet in ponds or even in bathtubs.”
Collaborating with Joseph Vinetz, a professor of medicine at UC San Diego and a leading expert in tropical diseases who has been working on developing vaccines against malaria, the researchers showed that the proteins produced by the algae, when injected into laboratory mice, made antibodies that blocked malaria transmission from mosquitoes.
“It’s hard to say if these proteins are perfect, but the antibodies to our algae-produced protein recognize the native proteins in malaria and, inside the mosquito, block the development of the malaria parasite so that the mosquito can’t transmit the disease,” said Gregory.
“This paper tells us two things: The proteins that we made here are viable vaccine candidates and that we at least have the opportunity to produce enough of this vaccine that we can think about inoculating two billion people,” said Mayfield. “In no other system could you even begin to think about that.”
The scientists, who filed a patent application on their discovery, said the next steps are to see if these algae proteins work to protect humans from malaria and then to determine if they can modify the proteins to elicit the same antibody response when the algae are eaten rather than injected.
Other UC San Diego scientists involved in the discovery were Fengwu Li from Vinetz’s laboratory and biologists Lauren Tomosada, Chesa Cox and Aaron Topol from Mayfield’s group. The basic technology that led to the development was supported by the Skaggs family. The research was supported by grants from the National Institute of Allergy and Infectious Diseases and the San Diego Foundation. The California Energy Commission supported work on recombinant protein production for biofuels use, and this technology helped enabled these studies.
Note: Materials may be edited for content and length. For further information, please contact the source cited above.
Gregory JA, Li F, Tomosada LM, Cox CJ, Topol AB, et al.Algae-Produced Pfs25 Elicits Antibodies That Inhibit Malaria Transmission. PLoS ONE, 2012 DOI:10.1371/journal.pone.0037179
Research by a collaborative group of scientists from UC San Diego School of Medicine, UC San Francisco and Wake Forest School of Medicine has led to identification of an existing drug that is effective against Entamoeba histolytica. This parasite causes amebic dysentery and liver abscesses and results in the death of more than 70,000 people worldwide each year.
(up) Entamoeba histolytica cyst. (Credit: UC San Diego School of Medicine)
Using a high-throughput screen for drugs developed by the research team, they discovered that auranofin — a drug approved by the US Food and Drug Administration 25 years ago for rheumatoid arthritis — is very effective in targeting an enzyme that protects amebae from oxygen attack (thus enhancing sensitivity of the amebae to reactive oxygen-mediated killing).
The results of the work, led by Sharon L. Reed, MD, professor in the UCSD Departments of Pathology and Medicine and James McKerrow, MD, PhD, professor of Pathology in the UCSF Sandler Center for Drug Discovery, will be published in the May 20, 2012 issue of Nature Medicine.
Entamoeba histolytica is a protozoan intestinal parasite that causes human amebiasis, the world’s fourth leading cause of death from protozoan parasites. It is listed by the National Institutes of Health as a category B priority biodefense pathogen. Current treatment relies on metronidazole, which has adverse effects, and potential resistance to the drug is an increasing concern.
“Because auranofin has already been approved by the FDA for use in humans, we can save years of expensive development,” said Reed. “In our studies in animal models, auranofin was ten times more potent against this parasite than metronidazole.”
In a mouse model of amebic colitis and a hamster model of amebic liver abscess, the drug markedly decreased the number of parasites, damage from inflammation, and size of liver abscesses.
“This new use of an old drug represents a promising therapy for a major health threat, and highlights how research funded by the National Institutes of Health can benefit people around the world,” said Reed. The drug has been granted “orphan-drug” status (which identifies a significant, newly developed or recognized treatment for a disease which affects fewer than 200,000 persons in the United States) and UC San Diego hopes to conduct clinical trials in the near future.
This work was supported by the Sandler Foundation and US National Institute of Allergy and Infectious Diseases grant 5U01AI077822-02, with additional support from R01 GM050389.
The above story is reprinted from materials provided byUniversity of California, San Diego Health Sciences, via Newswise.
Note: Materials may be edited for content and length. For further information, please contact the source cited above.
Anjan Debnath, Derek Parsonage, Rosa M Andrade, Chen He, Eduardo R Cobo, Ken Hirata, Steven Chen, Guillermina García-Rivera, Esther Orozco, Máximo B Martínez, Shamila S Gunatilleke, Amy M Barrios, Michelle R Arkin, Leslie B Poole, James H McKerrow, Sharon L Reed. A high-throughput drug screen for Entamoeba histolytica identifies a new lead and target. Nature Medicine, 2012; DOI: 10.1038/nm.2758
“Malaria tertiana is the form of malaria that science needs to focus on in more detail in future.” These are the words of Harald Noedl from the Institute of Specific Prophylaxis and Tropical Medicine at the Medical University of Vienna, spoken as part of World Malaria Day on Wednesday, 25th April. In a multi-centre study, the MedUni Vienna team, led by Harald Noedl, is working on an improved and more straightforward treatment of this form of malaria.
Although malaria tropica, which currently kills around 655,000 people a year (around 2,000 people every day), has increasingly been repressed as a result of more research, malaria tertiana may well develop into the main problem of the future in many countries, says Noedl. The problem does not so much involve the (low) mortality rate from malaria tertiana, but rather the often protracted period of illness that can occur as a result of the condition. This is because if the malaria tertiana pathogens are not killed with targeted therapy, they can remain dormant in the human liver for months or even years, and cause recurrent relapses.
Conventional therapy involves administering chloroquine for three days, followed by two weeks of primaquine therapy. “However unlike in Europe, compliance with medications in tropical countries is often very poor,” explains the malaria expert from the MedUni Vienna. Many patients would discontinue the medication after just a few days.
As a consequence, the pathogens will survive in the liver and can cause an outbreak of malaria tertiana at any time which is as infectious as the other two forms of malaria. This makes patients a constant source of infection for their environment and the new condition is often no longer associated with the previous episode of malaria and therefore treated incorrectly. Says Noedl: “This makes patients, most of whom are the poorest of the poor, constantly ill, preventing them from working. It’s a fatal vicious circle.”
In a multi-centre study involving the MedUni Vienna, scientists are well on their way to establishing a new substance (tafenoquine). The advantage of this is that the drug only has to be taken for a maximum of three days. Tafenoquine is currently undergoing clinical trials.
MedUni Vienna and new malaria focus in Africa
Since 2006, the Center for Geographic Medicine at the MedUni Vienna’s MARIB research center, led by Harald Noedl, has been working on malaria research in Bangladesh. More than 20,000 patients have been treated free of charge since. In 2012, the MedUni expanded its malaria focus to include Africa, and in particular Ethiopia. There, the MedUni team is cooperating with the University of Gondar in the north west of the country. Says Noedl: “We are keen to further the MedUni Vienna’s position as a leading centre for malaria expertise, lead multi-center studies and establish a global malaria network.”
Between 50 million and 100 million dengue infections occur each year, according to the World Health Organization.
VIRUS CARRIER: This picture shows the presence of the dengue virus in the mosquitoes’ chemosensory (antennae and palp) and feeding organs (proboscis). (Photo: Johns Hopkins Bloomberg School of Public Health)
Mosquitoes are already blood-sucking machines, but new research indicates that the dengue virus, which the mosquitoes transmit to humans, makes them even thirstier for blood.
The virus specifically turns on mosquito genes that make them hungrier for a blood meal; the activated genes also enhance mosquitoes’ sense of smell, something that likely improves their feeding skills. The result is a mosquito better able to serve the virus by carrying it more efficiently to human hosts.
“The virus may, therefore, facilitate the mosquito’s host-seeking ability, and could — at least theoretically — increase transmission efficiency, although we don’t fully understand the relationships between feeding efficiency and virus transmission,” study researcher George Dimopoulus, of the Johns Hopkins Bloomberg School of Public Health, said in a statement. “In other words, a hungrier mosquito with a better ability to sense food is more likely to spread dengue virus.”
The virus doesn’t hurt the mosquitoes that carry it, a specific species called Aedes aegypti, but it lives in them. When the mosquito bites a human, it spreads the deadly disease through its saliva. More than 2.5 billion people live in areas where dengue fever-infected mosquitoes live. The World Health Organization estimates that between 50 million and 100 million dengue infections occur each year.
The researchers analyzed the mosquito genes before and after being infected with the virus, finding changes in 147 genes. These post-infection genes make proteins that are involved in processes that include virus transmission, immunity, blood feeding and host seeking, they found.
“Our study shows that the dengue virus infects mosquito organs, the salivary glands and antennae that are essential for finding and feeding on a human host,” Dimopoulus said. “This infection induces odorant-binding protein genes, which enable the mosquito to sense odors.”
“We have, for the first time, shown that a human pathogen can modulate feeding-related genes and behavior of its vector mosquito, and the impact of this on transmission of disease could be significant,” Dimopoulos said.
This is just one of many recent examples of a parasite taking control of an animal for its own benefit. Other examples include a fungus that turns ants into zombiesand a virus that causes caterpillars to dissolve and then rain virus particles down on other potential hosts.
The study was published on March 29 in the journal PLoS Pathogens.
http://www.mnn.com/earth-matters/animals/stories/dengue-virus-increases-mosquitos-lust-for-blood by Jennifer Welsh, LiveScience
Sim S, Ramirez JL, Dimopoulos G (2012) Dengue Virus Infection of the Aedes aegypti Salivary Gland and Chemosensory Apparatus Induces Genes that Modulate Infection and Blood-Feeding Behavior. PLoS Pathog 8(3): e1002631. doi:10.1371/journal.ppat.1002631