Answers to Malaria
(appeared on 4th Dec 2013)

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It looks like a tool to control the malaria bug has been identified, says S.Ananthanarayanan.

So far, the malaria parasite, a single celled entity of a family called Plasmodium, has given the human race, particularly in the Tropics an exceedingly hard time. The parasite is spread by mosquito bite, and the hosts are vertebrates, like humans. At least ten species of the family Plasmodium affect humans and other species of the parasite also affect birds, reptiles and rodents. Usually, the female Anopheles mosquito infects people through its saliva, when it bites, for a blood meal. The parasite then breeds in the liver of the person bitten, to go forth and produce body symptoms, which can go as far as coma or death and also to pass on to other humans, via other mosquitoes that may partake of a meal of the infected person’s blood.

The parasite has proved well nigh impossible to control and some varieties have now become resistant to the most effective drugs. WHO data puts the number or malaria cases in the year 2010 at 219 million, with 666,000 to 1.2 million deaths, mostly of children in Africa. The two species that have serious effects, like death, on humans are P.falsioparum and P.vivax. All varieties are prevalent in Tropics, with ample rainfall and higher temperatures and they breed in stagnant water. Spraying and draining collections of water and the use of mosquito nets or repellants are measures of control, but with rising population and crowded living spaces, civil authorities seem to be waging a losing battle. In the context, the report of an international team, both industry and university based, in the journal, Nature, of discovery of a vulnerability of the malaria parasite at which drugs could strike for prevention, cure and control of transmission of the main varieties of the parasite that affect humans, is surely good news.

Malaria Infection

When the female mosquito bites, she transmits single celled, self-propelled precursors of the infection into the victim’s bloodstream. When these reach the liver cells, they multiply and produce another form of parasite, which infects red blood cells. In the blood cells, this form rapidly multiplies and when the cell bursts with the increase in numbers of its invaders, they go forth to infect more blood cells. Waves of such escape of parasites are marked by waves of fever in the affected person. Some members of this form of the parasite grow into a form that leads to creation of eggs which can start the cycle again. When a female mosquito bites and ingests this from of the parasite, the parasite matures in the mosquito gut and results in fresh parasites of the first form, which migrate to the mosquito’s salivary glands.

There are some standard treatment procedures and in the case of infection by P.vivax, both the blood cell stage as well as the earlier liver cell stage need to be treated, as P.vivax can stay dormant in the liver to cause delayed relapse. The only good drug for clearing the liver is Primaquine, but continued use of this drug is not possible, because of side effects and also because it is not so effective against the blood cell phase. As the mechanism of action of the drug is still not understood well directed search for radical cures has not taken place. What is needed, the authors of the paper in Nature observe, is to find and attack a target that is implicated in all the life –cycle stages of the parasite.

What they report

The authors report that a compound called imidazopyrazine, is found to inhibit the action of an enzyme, PI(4)K, used by the Plasmodium parasite at all stages of its development. The discovery of this enzyme may be the first time a suitable target for gaining control of the spread of the virus has been identified.

The team carried out tests of the complicity of this enzyme at the different stages of the life cycle – in incubation in the liver, the capacity for re-infection from stored remnants in the liver, the multiplication in the red blood cells and then the transmission of the reproducing variety to mosquitoes.

The first trial showed powerful blocking of one of the Plasmodium parasites that affects rodents by imidazopyrazine. The drug was found to be effective, in low doses, both as a preventive, when administered at the time of infection and also in clearing the infection when used after the infection had set in. And then, the liver-resident forms, which can cause delayed relapse, of another Plasmodium strain, were also cleared, by small doses of the drug. P.vivax, which stays in the liver to cause relapse in humans also showed sensitivity to imidazopyrazine, comparable to what was seen in the blood-cell stage of the more common P.falsiparum parasite.

During the blood cell stage also, it was found that the drug was able to block the development of numbers of the parasite that emerged from the liver. It was found that the drug interfered with the formation of viable instances of the second stage of the parasite, which multiplies in the blood cells. Infection of other blood cells, by the products of rupturing blood cells was found to be very low in the case of drug treated parasites, in comparison with controls, which shows that the drug brought about defects in the daughter products.

The last stage in the parasite life-cycle is that a small number of parasites in the blood cell stage differentiate into gametocytes, which are bodies that do not result in clinical symptoms, but lead to egg cells and continuation of parasite line. These are ingested by mosquitoes that bite and infected person and the then become capable of infecting other victims of their bite, through their saliva. These bodies are often not killed by the drug that may cure the patient of the disease, and the patient remains a source of infection to others or to himself or herself. The trials of the effect of the drug on the viability of gametocytes again showed that there was a marked reduction and as for transmission via mosquito bite, this was completely blocked.

As for the complicity of the PI(4)K enzyme, the team examined the mechanism of the action of different imidazopyrazines, by finding out just where some resistant forms of the parasite were different from the sensitive forms. Samples of the parasite were allowed to go through many generations and evolve into resistant forms. The genetic composition of the different forms were then compared and it was found that in all resistant forms, the change had occurred in the part of the genome, a single gene, which coded for PI(4)K. Different sub-trials, like allowing evolution without drug pressure, to lead to re-sensitisation as a result of correction of the defect in this same gene, established that it was PI(4)K that was the factor that resulted in imidazopyrazines having the inhibitor effect on the parasite.

The result is that PI(4)K has been identified as the drug target through which all the stages of the malaria parasite cycle can be addressed. “We anticipate that our findings will rapidly yield clinical candidates compatible with single exposure, radical cure and prophylaxis, a profile widely heralded as crucial for the success of worldwide malaria elimination efforts,” the authors of the Nature paper say.

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