Plasmodium falciparum parasites deploy RhopH2 into the host erythrocyte to obtain nutrients, grow and replicate

Abstract

Plasmodium falciparum parasites, the causative agents of malaria, modify their host erythrocyte to render them permeable to supplementary nutrient uptake from the plasma and for removal of toxic waste. Here we investigate the contribution of the rhoptry protein RhopH2, in the formation of new permeability pathways (NPPs) in Plasmodium-infected erythrocytes. We show RhopH2 interacts with RhopH1, RhopH3, the erythrocyte cytoskeleton and exported proteins involved in host cell remodeling. Knockdown of RhopH2 expression in cycle one leads to a depletion of essential vitamins and cofactors and decreased de novo synthesis of pyrimidines in cycle two. There is also a significant impact on parasite growth, replication and transition into cycle three. The uptake of solutes that use NPPs to enter erythrocytes is also reduced upon RhopH2 knockdown. These findings provide direct genetic support for the contribution of the RhopH complex in NPP activity and highlight the importance of NPPs to parasite survival.

DOI: http://dx.doi.org/10.7554/eLife.23217.001

eLife digest

Malaria is a life-threatening disease that affects millions of people around the world. The parasites that cause malaria have a complex life cycle that involves infecting both mosquitoes and mammals, including humans. In humans, the parasites spend part of their life cycle inside red blood cells, which causes the symptoms of the disease. In order to thrive, malaria parasites need to make the red blood cell more permeable so that they can absorb nutrients from the blood stream and get rid of toxic waste products they generate.

Previous research has shown that the parasites can produce a protein that makes red blood cells more permeable to a range of nutrients. Understanding how the parasites can do this, and if they could change the permeability of their host red blood cell to prevent anti-malaria drugs from entering may help researchers to identify new approaches to starve the parasite.

Counihan et al. investigated whether the parasites also use other proteins to modify red blood cells and demonstrated that a protein called RhopH2 can make the blood cells more permeable. The experiments used a genetically modified version of the parasite that lacked RhopH2. Counihan et al. show that essential nutrients and vitamins were depleted in these parasites and that the parasites were much slower to grow and reproduce.

The next important step would be to identify all proteins that are involved in making red blood cells more permeable and how they achieve this, and use this knowledge to help generate anti-malarial drugs.

DOI: http://dx.doi.org/10.7554/eLife.23217.002