Genetically Modified Fungus Could Fight Malaria

Bacteria use for producing anti-body against malaria are seen through a microscope at Westminster University in London, Tuesday, March 15, 2011. In a cramped London laboratory filled with test tubes, bacteria and mosquitoes, scientists are trying to engineer a new weapon in the battle against malaria: a mutant fungus. For years, Angray Kang at Westminster University and colleagues have been testing whether they could genetically tweak a fungus to kill the malaria parasite carried by mosquitoes.

NPR

In a cramped London laboratory filled with test tubes, bacteria and mosquitoes, scientists are trying to engineer a new weapon in the battle against malaria: a mutant fungus.

For years, Angray Kang at Westminster University and colleagues have been testing whether they could genetically tweak a fungus to kill the malaria parasite carried by mosquitoes.

Now they’ve found that in lab experiments, mosquitoes exposed to the fungus show a sharp drop in levels of the parasite. If it works that way in the wild, that should make it harder for the disease to infect people.

Kang said the mutant fungus could be sprayed onto walls and bednets like insecticides and could be made for a comparable cost.

He said the same process of genetic modification could also be used to target other insect-spread diseases like dengue and West Nile virus. The research was done together with scientists at the Johns Hopkins School of Public Health and was funded by the U.S. National Institutes of Health. Early results were published recently in the journal Science.

“This is very exciting research,” said Andrew Read, director of the Center for Infectious Disease Dynamics at Pennsylvania State University. He has worked on similar projects but was not involved with the fungus research. “It tells us that if you can’t find something in nature to do what you want, you can just make it.”

Read said using the souped-up fungus might be less environmentally invasive than other genetic approaches. Some critics have warned that competing biological approaches, like scientists creating mutant mosquitoes, could wreak havoc to ecosystems if billions of the insects are released into the wild.

With the fungus, “you just spray it on the wall and it does its job,” Read said. “You don’t have to worry about generation after generation of the stuff.”

He also said the fungus technology could be a new way of dealing with insecticide-resistant mosquitoes, an increasing problem that has meant the return of effective but controversial sprays like DDT. “With the (mutant) fungi, you wouldn’t have chemical residues hanging around,” he said. “It would just be a fungus very similar to what is already found in nature.”

In laboratory tests, Kang and colleagues found mosquitoes exposed to the mutated fungus had malaria parasite levels about 85 percent lower than normal. When they added a scorpion toxin to the mix, levels dropped by 97 percent. No tests have shown whether using the fungus would curb human malaria cases, but experts think fewer malaria parasites should translate into fewer cases.

“If the strategy works and there are fewer parasites, this could change how malaria is spread and reduce transmission to humans,” said George Christophides, an infection expert at Imperial College London who was not associated with the research.

Kang’s experiment involved inserting a human antibody against malaria into a fungus commonly found in soil and plants worldwide. Spores made by the fungus burrow into the mosquito, invading its circulatory system. When the malaria-causing parasite multiplies inside the insect, the antibody keeps the parasites from reaching the mosquito’s salivary glands. That theoretically stops the disease’s spread.

“The mosquito can be infected by malaria, but it can’t pass it onto humans,” Kang said. The mutated fungus then eats away at the mosquito from the inside, killing the insect after a couple of weeks. That’s long enough for the mosquito to reproduce, which should lessen its incentive to evolve resistance to it.

The same fungus — minus the genetic modifications — is already produced in industrial quantities to squash locust outbreaks in Australia. The fungus is naturally lethal to locusts, so no genetic modification is needed.

If Kang and colleagues can get enough funding, they hope to test the mutant fungus in malaria-endemic countries like Burkina Faso, Kenya or Tanzania.

Other experts doubted whether the laboratory experiment could be replicated in the wild. “It’s a neat scientific idea, but there are questions about (the mutated fungus’s) stability and formulation,” said Janet Hemingway, director of the Liverpool School of Tropical Medicine. She said the mutant fungus would have to survive being shipped to Africa and then be viable for another three to six months in stifling heat once it’s sprayed onto walls or bednets.

One group that campaigns against genetically modified organisms warned the mutant fungus could skew behaviors of other wildlife.

“The release of any genetically modified organism into the environment runs the risk that it may have wider impacts than just its target,” said Pete Riley, campaign director of GM Freeze, a U.K.-based advocacy group. He said the modified fungus could have unintended consequences which might be impossible to reverse. “Nature has a pretty cunning way of getting around everything we throw at it,” he said.

Kang acknowledged that simply having a new mutant fungus would not stop malaria. “We still need better drugs and other interventions,” he said. “But malaria kills about a million people every year so we have to try whatever may work.”

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Caught in The Act: Imaging Microscopy Catches Malaria Parasite Invading Blood Cells

Australian scientists using new image and cell technologies have for the first time caught malaria parasites in the act of invading red blood cells. The researchers, from the Walter and Eliza Hall Institute in Melbourne, Australia, and the University of Technology, Sydney (UTS), achieved this long-held aim using a combination of electron, light and super resolution microscopy, a technology platform new to Australia.

The detailed look at what occurs as the parasite burrows through the walls of red blood cells provides new insights into the molecular and cellular events that drive cell invasion and may pave the way for developing new treatments for malaria. Institute researchers Dr Jake Baum, Mr David Riglar, Dr Dave Richard and colleagues from the institute’s Infection and Immunity division led the research with colleagues from the i3 institute at UTS.

Dr Baum said the real breakthrough for the research team had been the ability to capture high-resolution images of the parasite at each and every stage of invasion, and to do so reliably and repeatedly. Their findings are published in today’s issue of the journal Cell Host & Microbe.

“It is the first time we’ve been able to actually visualise this process in all its molecular glory, combining new advances developed at the institute for isolating viable parasites with innovative imaging technologies,” Dr Baum said.

“Super resolution microscopy has opened up a new realm of understanding into how malaria parasites actually invade the human red blood cell. Whilst we have observed this miniature parasite drive its way into the cell before, the beauty of the new imaging technology is that it provides a quantum leap in the amount of detail we can see, revealing key molecular and cellular events required for each stage of the invasion process.”

The imaging technology, called OMX 3D SIM super resolution microscopy, is a powerful new 3D tool that captures cellular processes unfolding at nanometer scales. The team worked closely with Associate Professor Cynthia Whitchurch and Dr Lynne Turnbull from the i3 institute at UTS to capture these images.

“This is just the beginning of an exciting new era of discoveries enabled by this technology that will lead to a better understanding of how microbes such as malaria, bacteria and viruses cause infectious disease,” Associate Professor Whitchurch said.

Dr Baum said the methodology would be integral to the development of new malaria drugs and vaccines. “If, for example, you wanted to test a particular drug or vaccine, or investigate how a particular human antibody works to protect you from malaria, this imaging approach now gives us a window to see the actual effects that each reagent or antibody has on the precise steps of invasion,” he said.

Malaria is caused by the Plasmodium parasite, which is transmitted by the bite of infected mosquitoes. Each year more than 400 million people contract malaria, and as many as a million, mostly children, die.

“Historically it has been very difficult to both isolate live and viable parasites for infection of red blood cells and to employ imaging technologies sensitive enough to capture snapshots of the invasion process with these parasites, which are only one micron (one millionth of a metre) in diameter,” Dr Baum said.

He said one of the most interesting discoveries the imaging approach revealed was that once the parasite has attached to the red blood cell and formed a tight bond with the cell, a master switch for invasion is initiated and invasion will continue unabated without any further checkpoints.

“The parasite actually inserts its own window into the cell, which it then opens and uses to walk into the cell, which is quite extraordinary,” Dr Baum said. “Visually tracking the invasion of Plasmodium falciparum into a red blood cell is something I’ve been aiming at ever since I began at the Walter and Eliza Hall Institute in 2003; it’s really thrilling to have reached that goal. This technology enables us to look at individual proteins that we always knew were involved in invasion, but we never knew what they did or where they were, and that, we believe, is a real leap for malaria researchers worldwide

This work was supported by the National Health and Medical Research Council, The University of Melbourne, Canadian Institutes of Health, the University of Technology, Sydney, and the Australian Research Council.

This image is a composite showing the behavior of different parts of the malaria parasite as it invades a red blood cell, at nanometer scales. The three components of the malaria parasite are labeled with fluorescent proteins (blue = parasite nucleus, red = secretory organelle, green = tight junction). The red blood cell is superimposed on the image for context. Image 1 (Attachment): The parasite is about to invade the red blood cell (unseen to the right of the picture). The tight junction (green) is like a window that the parasite brings with it and inserts into the red blood cell to gain entry. Image 2 (Invasion): This image is mid-invasion, the first time this step has even been visualized. The parasite "opens" the window it has inserted into the cell, and walks through. The secretory organelle (red) secretes its contents through the tight junction (green) and creates a vacuole which the parasite lives within in the red blood cell. In this image we see the parasite nucleus (blue) moving through the ‘window’ into the cell. Image 3 (Sealing): The parasite has completed invasion and is within a vacuole inside the host red blood cell. The window has been closed again, and will break down at a later stage. The parasite is now enclosed within its vacuole (red), the nucleus (blue) showing the parasite safely inside.
Penny Fannin
fannin@wehi.edu.au
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A Breakthrough in Malaria Research

Scientists from Scotland have reported a major breakthrough  in fight against malaria.

The team from Edinburgh University in collaboration with  a team in Portugal  have discovered a gene that offers the drug resistance trait to the parasite. Drug-resistant plasmodium falciparum parasites are a major hindrance in the battle against the deadly disease. Chloroquine, the most commonly prescribed medicine against malaria has lost its effectiveness due to the proliferation of chloroquine resistant parasites.

Scientists think this is a  major development in malaria research. Malarial kills one to three million people annually, mostly children. These findings may pave a way for a new class of anti-malarials.

The study has been published in Biomedical Central (Sept 2010)

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