Yesterday I saw Dr. Alan Cowman give a talk. He's a big guy in the Plasmodium field. Plasmodium is strange. It's the eukaryote parasite that causes malaria. But that's not why it's strange. Let's put it this way, if animals, plants and fungi are three siblings, Plasmodium would be their 6th cousin who lives in a trailer-park on the other side of the river. It's a distant relative, but deep down they're all related in an uncanny way.
Take the Plasmodium genome, about 60% of the genes have absolutely no discernible features. In other words we can't even ascribe a domain to more then half of this parasite's genes.
But take a look at how Plasmodium invades a red blood cell (image on the right). It first nudges up along side of the host cell, then polarizes towards its new home. It sends out a long protrusion and forces the red blood cell to take it up by a forced macro-pinocytosis. Looking at Dr Cowman's micrographs I got a funny suspicion that I've seen this shape change before. And then it hit me, plasmodium is like a shmooing yeast cell!
When yeast mate, the two haploid cells grow towards each other and this morphological change is coupled to various intracellular changes. Click here to see a hot steamy movie of a yeast cell shmooing orgy. (It's actually pretty sad, the poor guys are all trying to have sex with a pipette).
Since actin is the major morphology driving polymer in eukaryotic cells, it was no surprise that actin was largely responsible for allowing the Plasmodium to invade the red blood cell. To figure out how the Plasmodium cytoskeleton was regulating actin dynamics the Cowman lab performed a bioinformatic analysis of Plasmodium actin regulatory genes.
Here's what they got:
Note that the varrious Plasmodium species do not have many genes. They don't have members of the Arp2/3 complex, a machine that drives actin polymerization to form actin meshwork. But they do have formins, a molecule that forms leaky caps at the growing end of actin filaments and catalyzes the formation of long actin polymers.
So where is the Plasmodium formin located in these polarizing cells? Exactly where you would expect it to be if Plasmodium was a shmooing yeast. It looks like Plasmodium forms new actin filaments at the leading tip and then transports it to posterior side of the celll by myosin ... just like in yeast and in mammalian cells. Where are all the membranous organelles? Right up alongside the actin rich membrane, just like in yeast. And the nucleus? At the back of the cell, just like in a migrating fibroblast. I bet that Plasmodium's MTOC orients towards the leading tip. It's all the same freakin' thing. I wouldn't be surprised if the whole orchestration of polarity in Plasmodium was regulated by small GTPases. The setup of polarity in eukaryotes is so conserved, it is incredible.
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Very interesting! I never thought about the way it gets nto RBCs - I was always focused on the way it gets out (it involves a melatonin receptor which, unlike ours, is a membrane receptor).
Ahhh if only it were that simple! Indeed, that's what we hoped it would be... but unfortunately its not.
A few corrections are needed here. First of all malaria parasites (indeed all Apicomplexa � the phylum of these distant cousins) do not need host cell actin to invade (remember red blood cells do not have dynamic actin). So this means that invasion is entirely parasite driven so no host macro-pinocytosis. Secondly, no membrane protrusion (or certainly no visible protrusion) occurs. Instead the parasite drives itself in by anchoring onto surface receptors by its own secreted adhesins and then drives itself in using an internal actin-myosin motor. I like to think of it like an old Viking war ship with oarsmen down each side. If you are interested check out this animation of how we think it all works [http://www.cell.com/trends/parasitology/supplemental/S1471-4922(04)0025…] (note the animation is of a Toxoplasma gondii parasite moving - but its thought that they all use the same basic motor to move and invade cells).
Finally, no small GTPases. In fact, the regulatory pathways you'd expect (the ROCKS, LIMs, WASPs etc) from the cellular world so many in cell biology are familiar with are all absent. The formins (profilin, cofilin and a few others) are the exceptions � making this parasite one of the ultimate actin regulator knockouts!
So whilst there are amazing parallels in what happens in malaria and yeast there also appear to be some substantial differences. In fact that's what we're banking on. Such differences might just allow us to target something malaria-specific, throw a spanner in its ability to move and therefore stop disease!
Jake,
Glad you stumbled upon my meagre post. Yes, you are correct in that the RBC has no pinocytosis machinery. However the plasmodium proteins likely to act in RBC invasion look strikingly like those in yeast. And as for small GTPases, do you in fact know that they are all dispensable? I would be quite surprised. As for ROCK, LIM and WASP, all GTPAse effector molecules, these seem to be the least important for general polarity in yeast and mammalian cells, in fact formins seem to provide the main driving force for polarization downstream of the small GTPases. And if small GTPases are involved you may want to target them, as many small bacterial proteins have been found to specifically inhibit each GTPase. For example, the C3 botulism protein specifically ADP ribosylates Rho and no other GTPase. Similar proteins inhibit Rac and Cdc42.
Anyway good luck, and let me know when the next publication comes out.