Now in order to successfully infect a human being, P. falciparum cells must deal with the immune system. The immune system is exquisitely good at destroying foreign invaders, which is why you are alive to read this. So in order for an organism to survive within your tissues and bloodstream it must have a way (or ways) to deal with your immune system. Some organisms simply destroy important parts of the immune system, helper T-cells in the case of HIV, thereby short circuiting the entire system. However, Plasmodium spp, at least the ones that infect mammalian hosts take a different approach. They duck and weave.
|Mickey: "I said duck and weave!"|
|From the CDC. We are dealing primarily with the bottom right blue circle.|
|Marti figure showing Plasmodium within a PV.|
Now everything is well and good from Plasmodium's perspecitve, it can get enough food. However, it still interacts with the more distal environment, the bloodstream, which means Plasmodium needs to make proteins that enter the PV, cross the PV membrane enter the red blood cell cytoplasm, and then enter the plasma membrane of the red blood cell to be able to see what's going on in the bloodstream!!!
The major protein that actually does this is called the Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1 for short). For the record, an erythrocyte is a fancy word for red blood cell. So PfEMP1 is out there interacting with the bloodstream doing all the things it needs to do, which is primarily interacting with other host (your) cells.
Sounds like everything is kosher for Plasmodium right? Wrong. Once this protein, which is made by a foreign invader, is exposed on the bloodstream, your immune system can see it. You may recall that your immune system kicks ass, so once it sees this PfEMP1 protein hanging out, it will ramp up the defenses and kill the red blood cell (including the growing Plasmodium cells within it). YAY! for you, boo for Plasmodium. It can also kill any RBCs infected with Plasmodium expressing PfEMP1.
Obviously, malaria wouldn't kill 3 million people a year if it let the immune system kick its ass. Nope Plasmodium learned long ago (yes Im anthropomorphizing) that sticking PfEMP1 out of the red blood cell is essential yet lethal. To overcome the lethality (from your immune system), Plasmodium encodes ~60 slightly different PfEMP1 proteins. As the immune system ramps up its defenses against one specific PfEMP1, a small subset of Plasmodium cells express a different PfEMP1 protein. The immune system kills off the red blood cells infected with the Plasmodium expressing the original PfEMP1 protein, but is completely unaware of the PfEMP1 protein being expressed. These new Plasmodium grow like mad, killing more red blood cells, until the immune system resets and notices the new PfEMP1 protein and the system repeats. All the while you are losing more and more red blood cells and your immune system is becoming less efficient because you are tired and weak. Ultimately you will die or your immune system will finally gain an edge (6-12 months later) and you recover.
This process of swapping proteins to avoid the immune system is referred to as antigenic variation, antigenic switching, phase variation, phenotypic switching, etc. Probably the best known example of this is the Trypanosomes (the topic for another post).
A Plasmodium cell is thought to only express a single form of PfEMP1 on the red blood cell. Upon infection of a new red blood cell, the specific form of PfEMP1 to be expressed can change in a very small subset of cells, but still only a single form of PfEMP1 is expressed. This is the "duck and weave" strategy mentioned above. However, a recent report in PLoS Pathogens suggests that things may not be so clear cut as one type of PfEMP1/red blood cell.
|Adapted from Figure 1 of Joergensen et al.|
|Adapted from Figure 6 of Joergensen et al.|
|Adapted from Immunobiology Figure 2.36|
Finally, it is quite simple to conclude that more binding is better and therefore infected red blood cells must frequently express distinct PfEMP1s. However, this may not be true. First, there is much evidence that infected red blood cells only express a single PfEMP1 type at a time. In fact, if different PfEMP1s were expressed at the same time, the immune system would be able to recognize them, which would more or less cause Plasmodium to duck into the punch. Second, it is unclear if this actually happens in the host or is an issue with laboratory culturing. Regardless, this paper clearly suggests new questions, which heretofore would not have been asked because it was well known that Plasmodium-infected red blood cells only express a single type of PfEMP1.
Joergensen, L., Bengtsson, D., Bengtsson, A., Ronander, E., Berger, S., Turner, L., Dalgaard, M., Cham, G., Victor, M., Lavstsen, T., Theander, T., Arnot, D., & Jensen, A. (2010). Surface Co-Expression of Two Different PfEMP1 Antigens on Single Plasmodium falciparum-Infected Erythrocytes Facilitates Binding to ICAM1 and PECAM1 PLoS Pathogens, 6 (9) DOI: 10.1371/journal.ppat.1001083