Plasmo ‘die’ uhmm? False-Ipa-room?

(First of two parts)

I do admit the title of my article sounds like a Yugoslavian tongue-twister whose meaning seems elusive to many, though in the field of medicine and parasitology, it is a word that signifies a complex microorganism causing a hematoprotozoan parasitic infection commonly known as malaria. Plasmodium falciparum, the main causative agent of malaria, was discovered over a hundred years ago and yet it is still responsible for 1.5 million to 2.7 million deaths annually. The disease continues to affect 40 percent of the world’s global population and represents 2.3 percent of the world’s disease burden, making it one of the most important parasitic diseases of man. The biological complexity of the parasite is made even more complex because of its infective ability and adaptation, enabling the parasite to involve a mammalian host during the completion of its life cycle. The infection results in life-threatening anemia for children and infants while pregnant women are susceptible to induced coma and primagravidae due to the placental sequestration of the parasite. Deaths commonly result from severe anemia, mild acidosis, pulmonary edema and cerebral malaria.

Resistance and transmission

The effort to control malarial infection today lies in the prevention of the spread of the mosquito vector (i.e., through the use of nets, insecticides) and the application of antimalarial compounds for case management. Antimalarial compounds commonly used for the treatment include quinine, chloroquine, mefloquine and sulfadoxinepyrimethamine. If you apply the classic quote "What does not kill me can only make me stronger" with the Plasmodium, then you get antimalarial drug resistance. Indeed, P. falciparum is now highly resistant to chloroquine in most malaria-endemic areas. Sulfadoxinepyrimethamine and mefloquine resistance is currently widespread and developing rapidly. The only antimalarial compound reported to have no trace of plasmodium resistance is the arteminisin. This compound is currently an essential component for treatment but if Plasmodium resistance to it develops, then we would be faced with untreatable malaria. Perhaps, the development of a newer method of control is difficult since the basic biology of the parasite and its unique mode of infection have not been fully investigated.

When I was young, I should have answered the popular adult question, "Who would you like to be when you grow up?" with "I would want to be like the Plasmodium, sir." If P. falciparum were human, it would have obtained its Ph.D. and post-doctorate in two years’ time or less because of its intelligent niche and technique for propagation. P. falciparum completes its schizogony (asexual cycle) in the red blood cells of vertebrates (that include us) and sporogony (sexual cycle) in its carrier, the anopheline mosquito. Immediately after the Anopheles bites, the Plasmodium parasite enters our body and invades the immune system by sequestering the liver until it is mature for the next cycle. After pre-maturation, the parasite (now called a merozoite) invades the red blood cells, causing structural deformation and re-orientation of the cell membrane, and sequesters there until it matures into male and female gametocytes, upon which the red blood cells will rupture, releasing the gametocytes in the blood stream waiting to be ingested as blood meal by another Anopheles mosquito. What makes this parasite so clever is its ability to fool or deceive our immune system (that releases antibodies specific for an antigen due to an invasion of any foreign material). Not only is the infection "strain-specific," it is also "variant-specific." A single strain can produce different variants of antigenic proteins. In the erythrocytic stage, the merozoites infect the red blood cells and different parasitic proteins are formed in the RBC membrane to aid in survival, serve as a marker and assist other adhesion processes. One important protein antigen is the Plasmodium falciparum Erythrocytic Membrane Protein1 (PfEMP1). This protein is highly polymorphic and has evolved to have 60 copies of its gene in each genome, therefore enabling it to change! However, even if there is a change in DNA sequence, the activity or function of this PfEMP1 protein is still conserved! One example is its ability to bind to the human endothelium through its Cysteine Rich Interdomain Region1. This primitive property enables the PfEMP1 to anchor itself to endothelial CD36 and avoid spleen-dependent killing.

And yes, the acute, specific and polymorphic cleverness of this parasite is the primary reason why scientific researchers are having difficulty in developing a vaccine. To make things more complicated, each of the different maturity stages of the parasite is marked by different proteins. Examples of these proteins are the circumsporosite for the hepatic sporocyte stage, the PfEMP protein for the erythrocytic stage, and the Pfs25 protein for the oogenic stage.

Although the possibility of an anti-malarial vaccine seems difficult to see due to the nature of the parasite, there are clever ways to overcome the barriers imposed by the P. falciparum. How does an amateur such as myself propose to meet each challenge? Let us see. (To be concluded)

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Francesca Diane M. Liu completed her Bachelor’s degree in Biochemistry at the University of Santo Tomas in 2002. She is finishing her Master’s degree at the University of the Philippines. She is currently working at the UP-Marine Science Institute as a research associate in Dr. Gisela Concepcion’s Marine Natural Products Laboratory and involved in the isolation of novel and biochemically active compounds from marine sources. She is also involved in sequence analysis and structure elucidation of the CIDR1-CD36 binding region of the PfEMP protein in P. falciparum-infected erythrocytes. E-mail her at fdiane_liu@hotmail.com