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Malaria is one of mankind’s oldest known killers, with descriptions of the disease dating back almost 5000 years. Each year, malaria causes 300-500 million infections, and up to 3 million deaths–about 5000 Africans die of the disease every day; one child succumbs every 30 seconds. The disease is caused by a number of species of the Plasmodium genus. (In humans, malaria is almost always caused by one of four species: Plasmodium vivax, Plasmodium ovale, Plasmodium falciparum, and Plasmodium malariae, with P. falciparum causing the most severe disease). Unlike many pathogens I discuss on here, Plasmodium is a protozoan–a eukaroyte with a nucleus, like you and I. It also has a very complex life cycle, going through different stages in its mosquito and vertebrate host. (I presented a short overview of this previously in this post on potential malarial vaccines). Though vaccines may be available in the future, prevention today is largely via control of the mosquito vectors using insecticides and mosquito netting. However, mosquitoes are growing increasingly resistant to the insecticides, and many people living in at-risk areas lack the financial means to purchase bed nets.
There are anti-malarial drugs to treat the patient once they’ve already been infected, but these, too, are losing their effectiveness due to parasite evolution. Additionally, a single infection does not confer life-long immunity. Not only can an individual be infected with different species of Plasmodium, but the parasite can switch the antigens it presents–the proteins on the parasite surface that the immune system recognizes. A recent study published in the journal Nature sheds some light on just how P. falciparum switches these antigens.
A question asked is how does P. falciparum regulate expression of the var gene family, a highly polymorphic family of genes which encode the P. falciparum erythrocyte membrante protein 1(PfEMP1). PfEMP1 is a major virulence factor that plays a role in immune evasion. In each individual P. falciparum parasite, only one var gene is expressed; the other 59 are silent. However, the parasite can switch expression: a parasite that initially expresses, say, var29 can switch and later express only var 40, for instance. This would protect the parasite, as a host that was mounting an immune defense targeted to the protein produced by var29 would have to essentially start back at square one. This was previously known, but what wasn’t known was just how P. falciparum carries out this switching, and more importantly, just how it keeps the other 59 silent while expressing the one of choice.
They found that it’s all about the promoter, baby–specifically, the upsC var promoter. When the parasites enter the bloodstream after the mosquito takes a meal, they invade the red blood cells (RBCs) and replicate. Once inside, PfEMP1is expressed on the surface of RBCs that are infected with the mature stages of P. falciparum parasites. What does PfEMP1 do here? From this paper:
[ PfEMP1] appears to play a central role in the adhesion of parasitised RBCs to specific receptors in the host micro-vasculature, and is thus critically important for the survival of the parasites because it prevents destruction of the infected RBCs during their passage through the spleen.
While most of the parasite population will express the same var gene, a small portion will express a different var gene. Then, when the host immune system eliminates the larger population, the minority population will take over, with another switch variant the immune system hasn’t seen waiting in the wings. This switch is controlled by the upsC var promoter.
Therefore, var promoter activation is a crucial step in control of allelic var exclusion because transcriptional activation of one var-associated locus inhibits transcription of the remaining var loci.
I know, that’s a mouthful (and the whole paper is like that–one of the densest I’ve read in a long time). Essentially, the transcription of one of those 60 var genes blocks transcription of the others–until a switch is thrown. The next step is to identify the exact proteins and mechanism involved in this activation.
Besides just being an interesting study, this has potential practical applications–specifically, antimalarial drugs. What if this switch could be blocked, so that the organism only gets one chance at infection? Or broken, so that the protein didn’t make it to the cell surface at all? Pfemp1 is also being investigated as another potential vaccine candidate, so an understanding of its regulation during infection can aid in that aim as well. A recent funding shot in the arm by the Bill and Melinda Gates Foundation certainly can’t hurt, either. Unfortunately, we still have a very long way to go before we get a handle on this pathogen.
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