Recently I have been learning about the malarial parasite Plasmodium falciparum for an impending PhD interview. One aspect of this which I find particularly interesting is the methods used by the parasite to evade the human immune system and how this can have an impact on the severity of the disease. A short disclaimer is probably wise, since I am not an expert on this stuff and I have only heard about a lot of this for the first time recently. Hopefully you can look forward to more (and better informed) posts about malaria in the future (lucky you!).
How malaria works
There were over 200 million cases of malaria in 2012 leading to an estimated 660,000 deaths. Plasmodium falciparum is the parasite responsible for the largest number of malaria cases in the world, and the highest mortality rate. Hosts can be repeatedly infected, with infections being most severe in babies and young children (and tourists) who have had little or no previous exposure. Total immunity is never acquired naturally, although repeated infection produces partial immunity and can produce asymptomatic infections.
The parasite has a complicated life cycle. The human part is summarised by the below diagram (drawn by pakasuchus). It is spread to humans by Anopheles mosquitoes, entering the human blood stream when an infected mosquito bites to feed. An important part of the life cycle involves merozoites entering red blood cells (RBCs) to replicate before bursting out of the cells to infect more RBCs.
Your immune system learns how to recognise specific molecules (called antigens) on the surface of pathogens (disease causing agents) or infected cells. This means once it has seen an antigen it is able to recognise it quickly and prevent reinfection. Antigens are targets for the immune system to latch onto, which also serve a useful function for the pathogen. There is no sense in presenting additional targets for a host’s immune system if they do not offer some kind of advantage.
An important antigen in P. falciparum is a protein called PfEMP1. PfEMP1 is is found on the outside of infected red blood cells (RBCs) to allow them to stick to different tissues. This takes the infected RBCs out of circulation, preventing them from being filtered out and destroyed by the spleen. This gives the parasite time to replicate while remaining hidden inside the infected cell.
Competing selection pressures
Natural selection acts on antigens in different ways. On the one hand, antigens serve specific functions and must retain that functionality in order to be useful. Antigens which are better at performing their function (in the case of PfEMP1, adhesion) give the parasite an advantage over individuals which use less efficient antigen variants. This selection pressure tends to produce populations with highly uniform but very efficient antigens. On the other hand, parasites need to avoid being recognised by the host immune system. To do this they must use antigens which are different from any previously encountered by the host. This selection pressure rewards parasites which use novel or unusual antigens, and leads to populations which are highly diverse. Thus, every parasite has to find a trade-off between immune evasion and exploitation of naïve hosts (those with no prior exposure to malarial parasites).
P. falciparum uses an approach called antigenic variation. Each parasite has multiple genes which code for variations of the same protein – in the case of PfEMP1 approximately 60 different variants are found in a single parasite, but only one is expressed. This means that inside one infected person, the malarial parasites can use different antigens despite being genetically identical.
PfEMP1 antigens have been classified into two groups; “conserved” and “diverse”. Buckee and Recker suggest that these conserved variants are useful when infecting naïve hosts because they work most effectively. However, they have little variation making them especially vulnerable to immune detection in non-naïve hosts. The highly diverse group is better suited for infecting non-naïve hosts. The high variation makes that it unlikely that a given host will already have encountered the antigen and be able to neutralise it. In this way, antigenic switching allows the parasites to choose either strategy depending on the situation, and effectively resolve the competing selection pressures.
This means malaria can get you whether you’ve had it before or not!
References and interesting things
- There are some really cool videos showing various stages of red blood cell infection by P. falciparum in the supplementary material here of a paper by Paul Gilson and Brendan Crabb. The paper and supplementary material are available here, but unfortunately they are not open access: http://www.sciencedirect.com/science/article/pii/S0020751908003780
- World Health Organisation 2012 Report on Malaria http://www.who.int/malaria/publications/world_malaria_report_2012/wmr2012_summary_en.pdf
- Gardner, M. J., et al., “Genome sequence of the human malarial parasite Plasmodium falciparum,” Nature, vol. 419, no. 6905, pp. 498-511, 2002. http://www.nature.com/nature/journal/v419/n6906/full/nature01097.html
- Recker, M., et al., “Antigenic Variation in Plasmodium falciparum Malaria Involves a Highly Structured Switching Pattern,” PloS Pathogens, vol. 7, no. 3, 2011. http://www.plospathogens.org/article/info%3Adoi%2F10.1371%2Fjournal.ppat.1001306
- Buckee, C. O., and Recker, M., “Evolution of the Multi-Domain Structures of Virulence Genes in the Human Malaria Parasite, Plasmodium falciparum,” PloS Computational Biology, vol. 8, no. 4, 2012. http://www.ploscompbiol.org/article/info%3Adoi%2F10.1371%2Fjournal.pcbi.1002451
- Kraemer, S. M. and Smith, J. D., “A family affair: var genes, PfEMP1 binding, and malarial disease.” Current Opinion in Microbiology, vol. 9, no. 4, 2006. http://www.ncbi.nlm.nih.gov/pubmed/16814594 (subscription).
- Smith, J. D., Deitsch. K. W., “Pregnancy-associated malaria and the prospects for syndrome-specific antimalaria vaccines“, Journal of Experimental Medicine, vol. 200, no. 9, pp. 1093-1097, 2004. http://jem.rupress.org/content/200/9/1093.full.pdf
Great article, thanks.
Interestingly PfEMP1 is implicated in the potentially fatal complication of cerebral malaria, associated with falciparum infection. Adhesion of the red blood cells to blood vessels in the brain (facilitated by PfEMP1 as you describe) blocks the blood vessels and restricts the blood supply to the brain.
e.g. – http://www.ncbi.nlm.nih.gov/pmc/articles/PMC26510/
Glad you enjoyed it! I’ll have a read of that article it looks interesting. I was thinking of writing a post about how different PfEMP1 proteins can result in different pathologies. There’s a nice diagram which sums up which PfEMP1 proteins contribute to which malarial pathologies in the Kraemer and Smith paper (same Smith) I referenced!