Male and female gametocyte cells in malaria parasite

Targeting male parasite cells during sexual reproduction could help to prevent malaria transmission, according to a new study.

Researchers from Imperial College London looked at cells in the malaria parasite called gametocytes, which are the reproductive cells responsible for transferring malaria from an infected human to the mosquito.

When a human is bitten by a malaria-carrying mosquito, the Plasmodium falciparum parasite enters the human’s bloodstream and invades their liver cells. Once established, they burst out into the bloodstream and invade red blood cells causing the host to fall ill. Less than one per cent of the parasites enter a sexual reproductive cycle, where they develop into gametocytes.

The new study, in the journal Antimicrobial Agents and Chemotherapy, shows that drug compounds with potential anti-malarial activity can make male gametocyte cells sterile. By inhibiting the further sexual development of gametocytes in a laboratory setting, the scientists were able to stop the malaria parasite from reproducing and multiplying.

Ultimately, the hope is that it might be possible to interfere with the sterility of male gametocyte cells so that if a mosquito bit an infected human, the mosquito would take up infertile male gametocyte cells, which would prevent further onward transfer of malaria. The researchers believe this is a promising new avenue for combating the disease.

Malaria parasite - P. falciparum - male gametocytes transform into gametes

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Until now, scientists developing antimalarial drugs have not differentiated between male and female gametocyte cells, as males are harder to detect and there tend to be many more females present. By separating the two populations for the first time, Imperial scientists discovered that male gametocyte cells are more sensitive to drugs than female gametocytes.

The scientists are now working with Medicines for Malaria Venture to identify and test drug compounds that only target male gametocyte cells, with the aim of accelerating promising drugs as quickly as possible into clinical trials. Dr Andrea Ruecker from the Department of Life Sciences at Imperial College London said: “At the moment most anti-malarial drugs treat the symptoms of malaria. People can get better, which is most important, but by only treating the symptoms and not the transmission of the disease, we will not get any closer to eliminating or eradicating malaria.

“Targeting the parasite’s sexual reproduction provides a potential way to permanently prevent the transmission of this deadly disease.”

Dr Michael Delves, also from the Department of Life Sciences at Imperial College London added: “Now that we know the male gametocyte is much more sensitive to drug treatment, we will be able to identify and prioritise drugs that only target these male cells. This new approach means that we will be able to increase the probability that drugs to block the transmission of malaria will be effective in the field.”

The scientists used a high-throughput screening approach to test the impact of different compounds on male and female gametocytes. This involved replicating the processes of malaria transmission at a cellular level, under laboratory conditions.

They began their tests by growing Plasmodium falciparum cells in human blood for 14 days as this is how long it takes for gametocyte cells to develop.

They then tested male and female gametocytes in a screening assay - using plastic tray with multiple wells which allows researchers to divide up the cells into tiny compartments to test many different drugs simultaneously.  

The scientists filled the assay wells with 400 compounds from the open access ‘Malaria Box’, which is a directory of compounds with known antimalarial activity provided free of charge by Medicines for Malaria Venture.

Microscopy and image analysis results showed that only six compounds affected female gametocytes. In comparison 19 compounds made the male gametocytes sterile and unable to move forward in the sexual reproductive cycle.

REFERENCE: Ruecker, A. et al. ‘A male and female gametocyte functional viability assay to identify biologically relevant malaria transmission-blocking drugs’. Antimicrobial Agents and Chemotherapy. December 2014. DOI: 10.1128/AAC.03666-14