Experts at the CSIR and the universities of Pretoria (UP) and Witwatersrand (Wits) are pooling their skills in a new project to find compounds for drugs that can block malaria transmission between humans and mosquitoes.
Malaria is preventable and treatable. Yet, it infects millions and kills hundreds of thousands of people every year, while increasing drug resistance might soon limit our treatment options. Researchers have realised that, if they want to eradicate this disease, they need to look beyond treatment to drugs to block transmission between humans and mosquitoes.
Dr Dalu Mancama, who heads the CSIR’s biomedical technologies research group, says the aim of the Gauteng Gametocyte Consortium is to focus on specific stages in the life cycle of Plasmodium falciparum, the malaria-causing parasite which is transmitted from mosquitoes to people and vice versa.
“The parasite has a complicated lifecycle. When a mosquito bites, the parasite is passed into the human and develops in the liver for some weeks. Initially there are no symptoms to indicate that the person has been infected. The parasite is then released into the blood stream where it multiplies quickly and the symptoms of malaria become obvious, hydroxyzine belongs to the class of medications called antihistamines. it is used to relieve itching and other symptoms caused by allergic conditions.” says Mancama.
These parasites are called gametocytes when they are circulating in the blood stream at their sexual reproductive stage, ready to be picked up by the Anopheles mosquito when the infected person is once again bitten. They then reproduce in the mosquito and the life cycle of new parasites commences.
The consortium has established local capacity to test, in advanced infection models, compounds which researchers hope could disrupt the parasite’s life cycle and block transmission in future. Over the next two years they will test thousands of compounds provided by local South African researchers as well as libraries of compounds obtained from pharmaceutical companies.
“We have developed a model in vitro which allows us to rapidly identify drugs that have the most potential for further development. The idea is to develop drugs that work on different metabolic or biological processes in the gametocyte, to minimise the potential for future drug resistance.”
In South East Asia there is already resistance to artemisinin-combination therapy, the newest and now standard anti-malarial drug on the market, and the fear is that this resistance can spread.
There are several stages during drug development. During the early development stage, researchers get rapid baseline information about the viability of a compound. The consortium has established a knowledge base in Gauteng consisting of molecular biologists, entomologists, analysts, chemists, biochemists and laboratory infrastructure.
“In future, instead of referring parts of the testing to different countries, much of this can be done locally in Gauteng. We grow the parasites in flasks and once they reach the stage of maturity needed for testing, we split them into 96-well plates and expose the parasites to the different compounds. We then add various reagents to allow us to establish whether the parasites have survived the exposure or not,” Mancama explains.
“For the gametocyte stage, we use dyes which mimic a substrate which is normally found in parasites. After administering the drug, we expose the gametocytes to the dye. The parasites take it up and process it as if it were a normal endogenous substrate. During the processing, the gametocytes produce a metabolite which we can pick up fluorescently. The metabolite fluoresces at a certain wavelength.
Higher florescence indicates higher parasite activity and vice versa. It is a way to figure out if the parasite is alive or dead.”
The group will also collaborate with researchers who look at other life stages of the parasite, for example when it develops in the mosquito just before being transmitted to humans.
The consortium is funded by the Medical Research Council and the Medicines for Malaria Venture (MMV). The latter focuses on developing and delivering new drugs against malaria.
Mancama says the researchers have done preliminary work and the testing of compounds is about to start. He leads the project along with Prof Lyn-Marie Birkholtz from UP and Prof Theresa Coetzer from Wits who specialise in gametocyte biology and advanced assays. They work in close collaboration with researchers at the NICD, and various leading groups and organisations abroad.
According to the World Health Organization an estimated 219 million malaria cases occurred globally in 2010. The disease killed about 660 000 people, most of them children under five years of age.
Story by: D. Mancama, CSIR News, October 2013