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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Comments

  1. #1 Dave S.
    January 16, 2006

    That is a really nice photo Tara.

    Another great reason to respect our friends the bats.

  2. #2 Josh
    January 16, 2006

    Question from a non-scientist:

    You say “Each year, malaria causes 300-500 million infections.” How can this be so? Wouldn’t that mean that everyone on the planet got malaria every 6 years? Or can you be re-infected with Malaria having become clear of the disease, meaning that hundreds of millions of people are infected with dozens of unique strains over the course of their lives? Or does this include re-emergence of dormant malaria in individuals?

    Thanks!

  3. #3 John Wilkins
    January 16, 2006

    The Plasmodium parasite also has a weird sex life. There are (from memory) 7 different mating types – 7 sexes, if you will – that depend on the stage of infection.

    Which goes to show that there are many mor einteresting ways of being alive than just being human…

  4. #4 Dave S.
    January 17, 2006

    Josh -

    I think it’s not only possible for an individual to have multiple malarial infections from different species of parasite, but also to have multiple infecions from different strains of the same species simultaneously.

    Tara could probably elaborate.

  5. #5 Tara
    January 17, 2006

    You say “Each year, malaria causes 300-500 million infections.” How can this be so? Wouldn’t that mean that everyone on the planet got malaria every 6 years? Or can you be re-infected with Malaria having become clear of the disease, meaning that hundreds of millions of people are infected with dozens of unique strains over the course of their lives? Or does this include re-emergence of dormant malaria in individuals?

    Yes, people can be re-infected many times due to the antigenic variation in the parasite. I’m not sure exactly how often it’s due to specifically to “dormant” malaria re-emerging with a different antigen versus a brand new infection, however. Also, remember that in addition to all the variability within the P. falciparum species, one can be infected with one of the other species as well, which generally tend to cause less severe disease.

    Finally, consider that malaria frequently infects young children–many of whom die. Meanwhile, there are new potential victims being born every minute to replace them.

  6. #6 Richard Sharpe
    January 20, 2006

    Hmmm, you say:


    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?

    How does each individual P falciparum detect that the host is on to it so it can switch its surface proteins?

    What if what is really happening is that the choice as to which surface protein is expressed in a new P falciparum individual is mostly like its parent, but, say, one in 100,000 cases is randomly different?

    In that case, the highest frequency phenotype will be overwhelmed by the host’s defences, but the genome survives … because the host will be continually infected by different phenotypes and thus one or more individual will survive to go on and infect another host.

  7. #7 Tara
    January 20, 2006

    Richard, that’s pretty much exactly what appears to happen. But still, according to their study, that 1 in 100,000 (or whatever fraction) is due to a variant in expression of the var gene, which is in turn controlled by the upsC promoter. So blocking that switch will eliminate the parasite’s ability to generate those 1/100,000 variants in the first place.

  8. #8 Anonymous
    January 20, 2006

    OK, I will have to read the paper to check the details then …

  9. #9 Tara
    January 20, 2006

    I should clarify–blocking the switch will *theoretically* keep them from generating those variants. Microbes are tricksty, they are, and may be able to get around a blocked upsC if given time and selection pressure.

  10. #10 Richard Sharpe
    January 20, 2006

    I realized what my confusion was. Not being a biologist by trade, but a computer type, I hadn’t realized that upon cell division, the daughther cell will have exactly the same surface proteins as the parent, since the daughter cell inherits about half of the parent’s cell surface. I had been thinking along the lines of the daughter cell being constructed from scratch …

  11. #11 Monado
    January 31, 2006

    I’ve often thought that if Plasmodium parasites had a science of evolution, it would be obvious to them that the higher the lifeform on the evolutionary tree, the more life stages it would have.

  12. #12 roger
    August 29, 2006

    mandame in spanish please

  13. #13 Eamon Knight
    November 10, 2007

    I’ve often thought that if Plasmodium parasites had a science of evolution, it would be obvious to them that the higher the lifeform on the evolutionary tree, the more life stages it would have.

    I recently read Zimmer’s Parasite Rex, which discusses Plasmodium along with many other biological infiltrators. Complex life-cycles, yeah. That Intelligent Designer was one inventive bastard!

  14. #14 marianne pienaar
    November 15, 2007

    I’m a paramedic and have been working with malaria patients for years, diagnosing, testing and treating.
    In Mozambique 2000-2003, Angola 2004, Zambia 2006, Angola 2007 Only had one person die of Cerebral Malaria in Zambia,Sometimes the locals get malaria once a month, every 2nd week, a couple of times a year, they have just had treatment and recovered and literally the next day they are infected again and then I see them about a week later for the headache and rigors and jointpain. I sometimes think that a malaria patient has a certain “look” about them. A Vaccine would be Great!

  15. #15 Gengoux P
    December 8, 2007

    Do you know how plasmodium attaches to red celles ?
    Dr. P. Gengoux

  16. #16 fina
    December 25, 2007

    thank’s for read my comments.
    can you give me some explanation about dengue haemorrhagic fever?is that have a same causes with malaria?
    thank’s for answer my comments.

  17. #17 ben
    January 16, 2008

    Hi Dr. Smith. I’m a chemist by education so a bit novice in this medical term. currently, my GF is having malaria and was confirmed by red blood cell microscope by the Dr. in Sentani Papua.
    She was given the traditional Kina (sp?)pill made from kina fruit. The hearing was temporarily lost but regain after 2 days later.
    The funny thing is the fever is still high after 3rd day of medication. Thus, we went to dept of health in Jakarta, Indonesia and was given artesdiaquine which consist of 4 tablets Artesunate 50 mg and 4 tablets Amodiaquine 200mg in 1 take.
    in about 1 hr, she threw up and all the food & medicine came out. And now the fever is 39.5 Celcius.
    I don’t know if this normal, but really appreciate it if you could tell us if we are following the right treatment for malaria?
    The last treatment is we are given doxycycline 500mg per day to take when we are back in Papua or other highly invested area. Really, appreciate your comment since we are schedule back to Papua next week once she recovers.

    Truly appreciate your inputs.

    Cheers,
    Ben

  18. #18 Reva
    December 23, 2008

    May I know about what kinds of malaria?
    I’m very drawn on this situation because it can make all people in my place can be ill.

  19. #19 Jesper Boldt
    January 5, 2009

    YEs, it sounds really good, but my wife in kazahazksthan has been killede by a bear. And my son Jinji, has a big cock, it’s grow 15cm after only 2 years, ampsemas.

    I love you alle, and i love sex.