Malaria, mosquitoes and man - breaking a deadly cycle

Malaria kills a child every thirty seconds in Sub-Saharan Africa, according to recent estimates. It is a huge problem currently threatening over 40% of the world’s population and still on the increase. The infection causes more than 300 million acute illnesses and at least a million deaths annually, and is recognised as a major factor impeding the development of some of the poorest nations.

Past strategies to kill off mosquitoes with insecticides failed as they developed resistance, just as malaria itself has developed resistance to some of the drugs used to control the disease.

Researchers at the Institute for Science and Technology in Medicine at Keele University, in the West Midlands region of the UK, are focusing their efforts on trying to break the transmission cycle through which the disease is passed on, by studying the complex relationship between the parasite and the mosquito itself.

Paul Eggleston, Professor of Molecular Entomology, School of Life Sciences, Keele University, said: “We have growing problems with insecticide resistance – we now have mosquitoes which are resistant to every class of insecticidal compound that we can throw at them, the parasites themselves are becoming resistant to all of the drugs we can use to try and tackle the disease. So we’re starting to think about this complex set of interactions that take place between the mosquito and the parasite and whether there are ways within that set of interactions that we can tackle the transmission cycle itself.”

Hilary Hurd, Professor of Parasitology, School of Life Sciences, Keele University, said: “I think one of the surprising things is that it takes so long for the malaria parasite to develop in the mosquito. It takes around 15 days and the mosquito in the wild often only lives that long. So it’s very much a tight rope that the parasite’s walking, it must keep it’s mosquito alive long enough for it to survive to transmit it once it’s infective, back into the next person. So that time period is the key aspect of the life cycle.”

One discovery of particular interest is that many of the parasites contained in the blood cells a mosquito absorbs during a blood meal, are killed off within the mosquito’s gut within the first twenty–four hours.

At Keele they think one method by which this is done is a means known as "programmed cell death", so they are investigating how this is triggered, and whether that action could be enhanced.

Another area of weakness they have discovered in this complex parasitic relationship is that the infected female mosquito produces fewer eggs. The likelihood is that this is a resource management strategy so the mosquito lives longer allowing the parasite to mature to an infective stage. If the mosquito was made to lay more eggs, it would die too early for the parasite to mature, again breaking the transmission cycle.

Professor Hilary Hurd: “If we can understand more about the biology and particularly the molecules involved and that are critical to maintaining the cycle then we can try to interfere with those molecules perhaps by manipulating the mosquito genetically so that a key molecule is produced in more abundance or is not produced at all and upset this delicate balance between infection and survival.”

While some researchers in Keele University’s Centre for Applied Entomology and Parasitology, are studying the biology of the mosquito, others are working on this genetic engineering approach, to see if they can inhibit the mosquito from passing on the parasite.

By injecting mosquito embryos with different genes with fluorescent markers that show up under ultraviolet light, they can track the genetically modified mosquitoes as they grow, and also see where the genes go. While they can introduce new genes, its not a precise process, and they can’t yet predict where they might end up in a chromosome, or whether they could damage existing genes.

Professor Paul Eggleston said: “The main limitation is simply one of efficiency. This is a very inefficient and technically demanding procedure, so at Keele we’ve been trying to think up new ways to get round these limitations and inefficiencies. One way is to introduce a docking site into the mosquito chromosome. This is simply a target into which we can integrate any new gene of our choice and we know that if the genes go into this target site they are going to be reliably expressed and we also know that they are not going to have a negative impact on any of the normal genes within the mosquito.”

The aim is to engineer a mosquito which is simply incapable of transmitting malaria.

Professor Paul Eggleston added: “What I would like to do with our new technology is to introduce a whole suite of transgenes, novel genes into the mosquito so we can have what I think of as a multi-hit approach. We want to be able to tackle the parasite at several different places within the insect all at the same time to make sure that no parasites survive and therefore we’ve effectively broken the transmission cycle.”

The ultimate vision is to replace natural populations of malaria carrying mosquitoes in disease endemic areas, with a “genetically modified mosquito” incapable of carrying the malaria parasite, and freeing large sections of the world’s population from the daily tragedy of young lives lost to this deadly disease.