BIG FAT POST ON PLASMODIUM
Or, "Everything I Could Think of Without Doing Research."
As requested by Eric and Cory.
Plasmodium is a genus of protozoan parasites (what your middle school teacher would have called a ‘protist’) that causes malaria in several species across the animal kingdom, most notably humans. It is transmitted from one individual to another by the Anopheles mosquitoes, a genus of mosquito which is currently confined to tropical regions of the earth. Malaria is endemic in most regions of sub-Saharan Africa, as well as South America and Asia. It’s not a particular vicious disease, at least not compared to something like AIDS, but since it’s so widespread that it’s among the big 3 infectious diseases receiving the most attention in terms of vaccine development and new drug treatments (along with TB and AIDS). About 2 million people die every year of malaria, most of them very young children. Almost all of these deaths are attributable to infection by species Plasmodium falciparum (as opposed to the other 3 species of Plasmodium). There are some subtle differences between the life cycles of the different species of Plasmodium, but I think everything I will be describing here is applicable to all species, except where noted otherwise.
Plasmodium’s life cycle can essentially be broken up into 3 stages:
1. Mosquito stage
2. Liver stage
3. Blood stage
1. Mosquito Stage
The parasites within the mosquito are horny little buggers, constantly having sex and recombining their genomes and creating all kinds of diversity. They replicate and then travel to the salivary glands of the mosquito, apparently causing the insect little or no discomfort and being generally noninfectious. When a mosquito takes a blood meal from some poor African kid, these motile parasites are injected into the bloodstream and quickly swim their way to the liver. If I recall correctly, the parasites first traverse a layer of immune cells called Kuppfer cells, by quite literally charging right through the cells themselves. This allows the parasites to reach the liver cells themselves, which they invade.
2. Liver Stage
During invasion, the parasite acquires part of the liver cell’s membrane, which it uses to separate itself from the rest of the cell. (Imagine blowing a bubble with some bubble gum, then pushing a rock into the bubble until the invagination closes on itself. Then the bubblegum surrounding the rock pinches off from the rest of the bubble, leaving a rock inside a bubble inside a bubble). The parasite then start to reproduce asexually, growing and dividing and stretching the limits of its envelope and the host cell itself. Eventually, through unknown mechanisms, the parasite escapes both its envelope and the liver cell itself, and shuffles its way back into the bloodstream.
3. Blood Stage
The blood stage of Plasmodium is much it’s liver stage, in that cells are being invaded, the parasite resides in a host-derived envelope, divides lots and lots, and escapes the host cell. As wikipedia describes the blood stage :
| Quote | | From the hepatocytes, the parasite replicates into thousands of merozoites, which then invade red blood cells. Here the parasite grows from a ring-shaped form to a larger trophozoite form. In the schizont stage, the parasite divides several times to produce new merozoites, which leave the red blood cells and travel within the bloodstream to invade new red blood cells. Most merozoites continue this replicative cycle |
As one might expect, this causes the destruction of a lot of blood cells, and leads to anemia, which in some cases can be quite severe. Some of the parasites differentiate back into the sexual form, which can be taken up when a mosquito takes a blood meal, and the cycle continues. Wikipedia also has an interesting hypothetical evolutionary scenario for the origin of this life cycle:
| Quote | | This life cycle is best understood in terms of its evolution. It is thought that Plasmodium evolved from a parasite spread by the orofaecal route which infected the intestinal wall. At some point this parasite evolved the ability to infect the liver. This pattern is seen in the genus Cryptosporidium to which Plasmodium is distantly related. At some later point this ancestor developed the ability to infect blood cells and to survive and infect mosquitoes. Once mosquito transmission was firmly established the previous orofecal route of transmission was lost. |
There is a pretty nice animation showing the whole process here:
http://www.sumanasinc.com/scienceinfocus/sif_malaria.html
var genes, pathogenicity, and immune evasion
During any infection, the pathogen must avoid detection by the immune system until it has multiplied enough to make transmission to a new individual easy. Plasmodium accomplishes this in a pretty interesting way. Most cells have a mechanism of presenting all the little bits of its innerds to circulating immune cells. The immune cells check to see if the presented bit is host-derived or foreign. If the immune cell recognizes foreign material, it will bombard the poor infected cell with nasty chemicals, leading to the destruction of both the infected host cell and it’s freeloader (for more detailed information, wiki or google MHC Class I and Cytotoxic T Lymphocyte). By infecting red blood cells, however, the parasite avoids this arm of the immune system. Red blood cells are enucleated, and thus don’t produce any DNA, RNA, or protein. They therefore lack any kind of machinery for blowing the whistle on the parasite which is living inside them.
However, living in red blood cells (RBCs) presents a different problem for the parasite. The cells are constantly circulating and must travel through the spleen, the organ responsible for destroying old and crappy RBCs. Through mechanisms which I do not understand, cells in the spleen are able to recognize infected RBCs, and destroy them. This is apparently not a total death blow to most species of Plasmodium, but it does appear to keep most infections from becoming lethal.
Except when it comes to Plasmodium falciparum. P. falciparum has evolved a mechanism to evade having to go through the spleen. When the falciparum parasite is within an RBC, it produces PfEMP1 proteins. These are encoded by var genes…
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To avoid confusion, or perhaps cause it:
DNA -> RNA -> Protein
Var -> var RNA -> PfEMP1
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The PfEMP1 protein is exported from inside the parasite all the way to the RBC surface. This process is extremely fascinating, as it requires the parasite to set up machinery outside of itself in order to properly transport the protein through the envelope in which the parasite resides and all the way to the RBC membrane. The parasite can’t co-opt host cell machinery, since RBCs don’t have any. This process is still being figured out. Anyway, the PfEMP1 protein is able to bind to certain receptors that are on the surface of the blood vessels. This tethers the infected RBC to the blood vessel, preventing the infected cell from reaching the spleen where it would be destroyed. PfEMP1 can also attach to uninfected RBCs, which essentially cloaks the infected RBC with uninfected RBCs, making it harder to “see.” Infected RBCs also can stick together, forming big ole clumps of cells. All this sticking is pretty bad, and becomes lethal when cells start clogging up passageways in the brain. Cerebral malaria causes hemorrhaging, and is one of the main causes of malaria-associated deaths (along with pregnancy malaria and severe anemia).
So the stickiness is all well and good for the parasite, but by putting a piece of itself on the surface of an RBC, it has exposed itself once again to the immune system. Before getting into the beauty of antigenic variation, I’ll need to do a quick aside on how adaptive immunity works.
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Adaptive immunity is absolutely ridiculous. Basically, when a T cell or B cell (henceforth lymphocyte) is made, the part of its DNA that encodes the T cell Receptor or B cell Receptor undergoes recombination that is pretty much random. There are enough possible permutations of the DNA to produce proteins that just happen to be capable of binding to just about any other protein. The lymphocytes that have receptors that can bind host cells are weeded out and destroyed, while ones that can’t are allowed to get into the blood stream and look for trouble. The body cranks out enough of these cells that just about any foreign protein can be recognized by a small handful of cells in the body (and there are ways that the body uses to increase the odds of this interaction occurring, which I won’t go into). Once a lymphocyte recognizes something (hopefully a pathogen), it will start dividing and cranking out antibodies (which are soluble B cell receptors, so are very specific), and the infection can be pretty quickly cleared. Some of the lymphocytes will differentiate into memory cells, which can start the process of cranking up the adaptive immune response to the same foreign material much more quickly than if the body had to start all over again.
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Back to malaria. The falciparum parasite has about 60 different var genes in its genome, but only expresses one at a time. The immune system recognizes the PfEMP1 protein on the RBC surface, cranks up a response to it and then… the parasite switches what var gene it is expressing, and hence changes the PfEMP1 protein on the surface. And the immune system has to start all over again. The switching of var genes isn’t fully understood, but it appears to be a general low rate of switching, followed by selection for newly exposed PfEMP1s, rather than a preprogrammed sequence of gene expression (but we DO see that in Trypanosoma brucei, the African Sleeping sickness parasite… but that’s another sto-ey). This process is known as “antigenic variation,” and is found in both protozoans and bacteria.
I mentioned that there are 60 different var genes in a given parasite. But it goes beyond that. Each strain of Plasmodium falciparum has a different set of var genes. If one strain is endemic in a region, eventually people’s immune systems will have figured out a good deal of the different var genes. But when a new strain enters the region, once again the immune system needs to learn a whole new set of proteins to recognize. Thus, it is beneficial to the parasite to have a different set of vars than its relatives, because it will evade the immune system more easily just by being different. Clearly, this shows a scenario where a very high proportion of mutations would in fact be good for the parasite, simply because they make the parasite look different.
The Theory of Evolution easily explains why there is so much var gene diversity amongst different strains of Plasmodium. Mutation creates the diversity, and diversity is selected for.
How does Dave’s UPDATED Creator God Hypothesis explain it? Were all the strains created as different kinds (and remember, these bugs had to have been on the ark, maybe in some poor hapless dinosaurs?), or did they gain all these special new abilities? Have the species of Plasmodium that lack var genes lost their ability to produce them, with God creating more lethal parasites to start with?
Please, Dave, what does your hypothesis predict for the origins of this nasty parasite and, in particular, the very valuable antigenic diversity contained between different strains? |
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