Host-targeted antibodies effective against malaria

Treatment that disables blood cell protein wipes out infection in three days

Host-targeted antibodies effective against malaria

150720-basigin.pngDOI:10.1084/jem.20150032

All antimalarial drugs produced to date target the disease-causing parasite, but a new study in the Journal of Experimental Medicine shows that drugs which target host proteins are also a potential avenue for new interventions.

This study targets a protein that the most deadly malaria parasite, Plasmodium falciparum, relies on to invade human red blood cells. Targeting this human protein blocks an essential interaction, and can wipe out an established malaria infection in mice in less than three days.

Targeting host factors may help researchers overcome one of the biggest challenges to malaria control: drug resistance. Drug resistance arises due to genetic changes in the rapidly-evolving Plasmodium falciparum parasite, which, in Southeast Asia, has rendered one of the current front-line antimalarials, artemisinin, largely ineffective. Researchers are battling to find a solution before the resistant strains spread to other malaria endemic areas, including Africa, a region that accounts for 90 per cent of malaria deaths worldwide. By targeting host factors, rather than the parasite factors, the researchers believe that parasites are far less likely to develop resistance to the new drug.

"This counter-intuitive approach to malaria treatment leaves the parasite powerless. If the parasite can't bind to the surface of our red blood cells and invade, it can't reach the next stage in its lifecycle, so it dies. There's nothing the parasite can do to get round it, as the interaction is absolutely essential for infection to occur."

Dr Zenon Zenonos, a first author from the Wellcome Trust Sanger Institute

PfRH5, a protein required by the malaria parasite, needs to bind to basigin, a protein that is displayed on the outer surface of human red blood cells, for the cell to become infected. Blockade of the PfRH5-basigin interaction renders the parasite unable to enter red blood cells, and therefore the infection is wiped out.

"When we discovered the PfRH5-basigin interaction in 2011, we knew we had found a chink in the malaria parasite's armour, the question was how to exploit it. Using PfRH5 in a vaccine is one approach, but we were also interested to see if we could disrupt the interaction in the opposite direction rather than by conventionally targeting the parasite. This has significant advantages in preventing the ability of the parasite to develop resistance."

Dr Gavin Wright, corresponding author from the Wellcome Trust Sanger Institute

To study the likely human response to therapy, the antibody targeting basigin described in this study was tested in humanised mice that have had the majority of their immune cells and blood cells replaced with those from their human counterparts. In the mice, levels of infection fell to essentially undetectable levels within 72 hours of being treated with low doses of the antibody targeting basigin. Importantly, no side toxic effects were observed in the mouse models that were treated with the antibody in these experiments.

"While the cost of producing and administering these drugs is currently relatively high, our hope is that future technological advances will enable this antibody to become a feasible response to malaria on the ground. Antimalarial resistance poses a huge threat to global health and the more options we have in our armoury, the better equipped we will be to fight malaria."

Dr Sara Dummler, a first author from the Singapore-MIT-Alliance for Research and Technology

Notes to Editors
Publications
  • Basigin is a druggable target for host-oriented antimalarial interventions.

    Zenonos ZA, Dummler SK, Müller-Sienerth N, Chen J, Preiser PR et al.

    The Journal of experimental medicine 2015;212;8;1145-51

Funding

This work was supported by the Wellcome Trust grant number 098051, and the National Research Foundation Singapore through the Singapore-MIT Alliance for Research and Technology’s Interdisciplinary Research Group in Infectious Disease research program.

Participating Centres

Wellcome Trust Sanger Institute, Singapore-MIT-Alliance for Research and Technology, Nanyang Technological University, Massachusetts Institute of Technology.

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