Blood invasion of Plasmodium falciparum is dependent on a single receptor on the surface of red blood cells

Posted by Kasra

Plasmodium falciparum parasites invade different groups of cells during their life cycle. Upon injection into humans, sporozoites pass through the skin and travel in the blood to be picked up by hepatocytes. After completion of the liver phase, merozoites come back to the blood and invade red blood cells. Finally, there is another sort of invasion happening inside the midgut of the mosquito, different from the vertebrate host. The invasion of red blood cells by merozoites is the most accessible of the three for studying. Of great scientific and theraputic interest are the proteins that allow for this binding and internalization of the parasites to occur. Blocking the blood stage of malaria would essentially abrogate the majority of its pathological complications.

Many surface proteins of Plasmodium and red blood cells had been previously proposed to be involved in this host-parasite interaction and binding. However, in almost all cases, great redundancy was shown in the protein-protein interactions; meaning that knocking out one surface protein or blocking one interaction would only replace it by another one. In some cases this would result in a change in the tendency of the Plasmodium parasites to bind mature vs. Immature red blood cells, but invasion would still happen. But now, recent work has found a definitive receptor for invasion of red blood cells by P. falciparum merozoites. The beauty of this work is not only in finally finding a ligand and receptor for this stage of P. falciparum life-cycle, but also in my opinion in making great use scientific knowledge already available for making this discovery. So here is the brief story for those of you who do not feel like reading this short yet elegant letter to Nature:

In search for a definitive receptor, Crosnier and colleagues decided to study a surface protein of P. falciparum that was found by another group to be essential for parasite growth: PfRh5. In order to find its binding protein, they went through the already published proteome of the red blood cell and picked up the secreted and surface expressed proteins. Using an ‘Avidity-based extracellular interaction screen’ (AVEXIS) they screened for binding of PfRh5 to recombinantly produced secreted or surface proteins of the red blood cell and luckily they got a single hit: Basigin or BSG. They then validated this direct interaction using Surface Plasmon Resonance and showed that the interaction occurs independently from glycosylations. Next, they showed that adding soluble BSG, blocking it by a specific antibody or shRNA knockdown inhibits invasion of red blood cells by all clinical and lab strains of P. falciparum. As I previously mentioned, inhibition of invasion was never seen before for any of the receptor-ligand pairs suggested.

Finding such a well-fit receptor for invasion of P. falciparum brings up an evident question: Are people with mutations in the bsg gene resistant to malaria? The authors found very few nonsynomymous single nucleotide polymorphisms (meaning SNPs that lead to a different protein sequence) in some populations in the databases. Blood donations from some of those SNP carriers showed actually resistance to P. falciparum invasion. Unfortunately, population genetics data is seriously lacking in areas afflicted with malaria, so whether this gene has been through positive selection or not cannot be determined at the moment. The authors are hopefull to be able to answer this question after some genome projects currently in progress in Africa are complete.

This ligand-receptor interaction appears to be specific to P. falciparum and other Plasmodium species have not been mentioned in the paper (I am pretty sure they have been checked). This makes in vivo drug testing difficult as P. falciparum is not used in the murine malaria infection model. Nontheless, P. falciparum is the most prevalent and lethal malaria-causing species. The discovery of BSG as a receptor for invasion opens many doors towards a generation of theraputics and prophylaxis, bringing us hopefully one step closer to its elimination.

Crosnier C, Bustamante LY, Bartholdson SJ, Bei AK, Theron M, Uchikawa M, Mboup S, Ndir O, Kwiatkowski DP, Duraisingh MT, Rayner JC, & Wright GJ (2011). Basigin is a receptor essential for erythrocyte invasion by Plasmodium falciparum. Nature, 480 (7378), 534-7 PMID: 22080952

TWIP: The ultimate podcast about parasites

Posted by Kasra

It has been more than a year since my last post. Apparently doing science has taken over writing about science. I am going to try to put more frequent updates which means that I get to explore research being done on parasites again! I would also like to state again that parasite diary would gladly accept your diaries as well. May it be your own research, or work by somebody else that you find fascinating. It doesn’t need to be recently published either. I am pretty sure nobody has read everything about everything. Therefore, all stories about parasites (whether eukaryotic or not) can be exciting and informative to read. If you are interested in participating, send us your diaries to  parasitediary AT gmail DOT com and we will publish them under your name.

As a start to the new era of the parasite diary, I would like to introduce a podcast  that I think anyone with the slightest interest in parasites should not miss. This Week in Parasitism (TWIP)  is narrated by Dr. Vincent Racaniello and Dr. Dickson Despommier from Columbia University. This podcast teaches you  about ecology, physiology and behaviour of eukaryotic parasites and tells you stories that you have never heard before about their history and impact on human life.  Their enthusiasm  for research and for parasites pumps up your energy to continue doing your boring benchwork while listening! I need say no more. Check out TWIP and its sisters (or brothers?) TWIV (Virology) and TWIM (Microbiology).

P.S. The picture in the logo of TWIP is of the nematode Trichinella spiralsis sitting comfortably inside its nurse cell in the muscle tissue.