I recently found a really great video about Malaria. Scientists have, for the first time, seen the Malaria parasite enter into a red blood cell. Check out the video below and then, if you’re really interested in Malaria, I’ve posted an essay I’ve done on how the Malaria parasite functions.
There are three billion people affected, 250 million people infected and one million people killed every year by Malaria1. In developing countries such as those in Africa, Malaria kills one in every five children1 and affects people of all ages and sex. The disease effects are found most in Africa where 89% of Malaria cases take place and, next to AIDS/HIV, is the leading cause of deaths in Africa4.
At first, the disease was thought to originate about 10, 000 years ago; the same time that agriculture was being formed. However, new research as recent as June 2010 indicates that this is not the case. It is now speculated that the disease originated as far back as 80, 000 years ago and evolved along with our ancestors before being spread around as human migrated out of Africa4.
The disease is caused from a parasite, formally called Plasmodium, which lives in humans and the female Anopheles mosquito. The Plasmodium parasite is a eukaryotic cell and is one of the smallest eukaryotic cells known. To put it in contrast, its mitochondrial genome is the smallest of all eukaryotes; containing only 6 kb and codes only three proteins2. The small size allows the cell to live inside other cells as if it were just another organelle, allowing it to feed off the host cell nutrients, multiply itself and even affect the host cell functions in many ways. Even though this cell is so small, it can have dire consequences on an infected person.
There are four different types of Plasmodium: P. falciparum, P. ovale, P. malariae and P. vivax4. Once the Plasmodium parasite enters the blood stream it can take up to 14 days for any symptoms to occur. It takes this long because the parasite requires this time to duplicate itself in its host before it can cause any damage. Some of the major symptoms of Malaria are headaches, high fevers, abdominal pain, chills and sweats, diarrhea as well as dizziness4. If P. falciparum is the infecting stream, more advanced symptoms can occur including extreme tiredness, comas, kidney failure and anemia4. The exact causes of these symptoms will be discussed later.
As earlier stated, Malaria has been around for quite some time and as a result has been researched and studied for thousands of years. As far back as 800 BC, people had associated mosquito bites with fever, disease, and shivering6. Modern day scientists have been trying to find treatments of Malaria and, in 1987, Dr. Manuel Elkin Patarroyo developed a vaccine6 to battle the Plasmodium falciparum. Understanding the cause of this disease can lead to better prevention, treatment and control of the spread of Malaria. While trying to understand the disease more, it was discovered that the parasite lives in a cycle involving two hosts: the mosquito and humans. It cycles between the two hosts and is constantly transforming into different forms of itself throughout many different stages.
Malaria’s lifecycle starts with the female Anopheles mosquito. This mosquito normally eats sweet nectars and fruit juices except when it is pregnant. While the female Anopheles is pregnant, it feeds off of human blood to supply its future progeny with nutrients. During the feeding process, the mosquito transfers saliva into the human and as a result injects sporozoites7 (an asexual form of the Plasmodium which is long and thin) into the human blood stream. Right away these sporozoites are directed to the liver where they enter into the exoerthyrocytic stage.
The exoerthyrocytic stage of the parasite takes place only in the liver. Here, the sporozoites, which are small eukaryotic cells, replicate themselves in the liver cells cytosol. The new cells are called merozoites and are more round than their previous form which was long and skinny7. The new merozoites escape the host liver cell to go and infect other liver cells. This process can take eight to fourteen days because it can take long periods of time to replicate the parasite the amount of times necessary. When there are enough newly formed cells, the merozoites are triggered to leave the liver cells. They leave the liver cells by way of exocytosis; they wrap themselves in the membrane of the liver cell and create a transport vesicle. The wrapping of the livers membrane around the cell allows the cell to evade the immune system of the human because the immune system is misled to think it is a liver cell, therefore doing nothing to stop the parasite3. Once the merozoites exit the liver cell, they find their way to the blood stream where they enter into the erythrocytes stage.
The word erythrocyte means red blood cells, indicating that the next stage takes place in red blood cells. Once the parasite enters the blood stream, it must recognize and enter into a red blood cell (RBC). Several signaling proteins are used by the parasite to find where the RBCs are, but what proteins are used in the signaling process is still unknown8. Once the protein finds an RBC, it binds to the signaling receptors on the surface and starts the invasion process. Invading starts when the merozoite creates a vacuole from the plasma membrane of the RBC8. Using a moving junction, the parasite enters into the vacuole and then enters into the RBC.
Now that the parasite is inside the RBC, it has two main functions to serve: one is to reproduce itself, and the other is to not get destroyed. Reproducing is relatively easy because the RBC provides all the nutrients (such as amino acids in hemoglobin and other proteins9) required for replication. Not being destroyed by the immune system is a more difficult. The RBC acts as a shield to any antibody because an antibody cannot recognize the parasite. However, an RBC follows a path around the body and will eventually end up going to digestive organs that can detect and break down the parasite (such as the pancreas). Therefore the parasite must find a way to stop the RBC from moving around.
Red blood cells move throughout the blood stream by rolling and turning. They have proteins (intermembrane proteins) on the surface that helps them achieve this movement. They also have two specific proteins on the surface that help them be stationary by binding to other cells. To activate these stationary proteins on the surface, the Plasmodium parasite encodes a protein called PfEMP1 (Plasmodium Falciparum Erythrocyte Membrane Protein 1). PfEMP1 is a larger protein that ranges in size between 200 and 350 kDa10. Its purpose is to control and take over certain functions within the RBC, including the proteins on the RBC surface to help the RBC bind to endothelium cells and other non-infected RBCs (termed resetting) initiating adhesion10 and stopping movement of the host RBC. Figure one shows the modified proteins and how they bind to other RBCs and endothelium cells.
Now that the RBC is in a stationary phase, the parasite no longer has to worry about being detected or moving throughout the body and can concentrate on duplicating itself. At this point the merozoite expands and transform again: this time into a trophozoite. A trophozoite is ring shaped and has a nucleus that divides asexually to produce many nuclei (this form is called a Schizont)7. The Schizont then divides to produce many more merozoites. With so many merozoites now in the RBC, the cell bursts releasing the merozoites to infect other RBCs and starti the erythrocyte process again on all nearby red blood cells. This bursting also releases toxins into the body which produces the fever and chills that are commonly found as a result of Malaria. In further developed cases of Malaria, the sudden bursting of many RBCs creates a drop in the number of RBCs in the body and is the result of anemia. Not having enough RBCs in the body leads to less oxygen transport throughout the body and can lead to increased sweating, vomiting and heartburn.
The final stage of the Plasmodium occurs when they enter a final transformation into gametocytes7. A gametocyte is either male or female and resides inside red blood cells. What triggers this final transformation is not entirely known, but it is hypothesized that it happens when a merozoite enters a younger RBC11. A younger RBC is found to be less dense than mature a RBC as well as contain more RNA and still synthesize hemoglobin11. This will provide a better environment for the parasite to develop because there are more nutrients. As well the 10 day transformation is more likely to occur here than in a mature cell because the lifespan of RBC is only ~120 days11. When the female Anopheles mosquito ejects blood out of the human it can also eject gametocytes into its blood stream. The mosquito is immune to the parasites harmful effects, but the gametocytes mate in the mosquito to produce sporozoites. The sporozoites are targeted to the salivary glands in the mosquito7, completing the cycle as the mosquito will inject its saliva into the next human it feeds on, spreading the parasite to a new human host.
The Plasmodium parasite lives within the human constantly disrupting cellular activities within the blood stream and liver. It has the ability to make an individual extremely ill and, if left untreated, can be fatal to a human. It is imperative to disrupt the spreading of the parasite and treat the infected before it causes more damage. For decades, researchers have been looking for treatments for the disease with some success. The drug of choice, for its availability and effectiveness on most strains of Plasmodium, is Chloroquine. Taken worldwide, Chloroquine enters a RBC by diffusion, and then transforms itself so it can no longer diffuse. Once permanently inside the cell, Chloroquine caps hemozoin12, which is a toxic byproduct of Plasmodium. Hemozoin is normally broken down, but with a cap on it, Plasmodium parasites can no longer break down leading to a buildup of the toxin12. This buildup serves fatal to the parasite and it eventually dies. Unfortunately, newer streams of Plasmodium are arising and the effectiveness of Chloroquine is slowly becoming weaker. Newer drugs are being researched, but are more expensive and they tend to be effective on single streams of the parasite.
The best way to stop the spread is through preventative measures. Something as simple as using a mosquito net at night can block mosquitos from transferring the parasite. In the most affected areas, these can be very expensive, but more initiatives are being brought forward to help make mosquito nets more affordable for developing countries where malaria is most prominent. Also, malaria pills can help stop the parasite from infecting humans and these are taken as an effective measure before travelling to susceptible countries.
In conclusion, the cycle of the Plasmodium parasite is one that can stop normal function of red blood cells and in affect, cause a variety of symptoms. If not treated fast, the parasite can lead to destruction of bodily function and can be fatal. In order to prevent further spread of the disease, action should be taken to protect ourselves and others and hindering the spread of the parasite from the mosquito to humans.
References
1) No Author (March 2009). 10 facts on malaria. World Health Organization. Retrieved November 24 2010, from http://www.who.int/features/factfiles/malaria/en/index.html
2) Cooper G., Hausman R. (2009). The Cell: A Molecular Approach, Fifth Edition. Washington, D.C.: ASM Press.
3) Sturm A, Amino R (August 3 2006). Manipulation of host hepatocytes by the malaria parasite for delivery into liver sinusoids. PubMed. Retrieved November 24 2010, from http://www.ncbi.nlm.nih.gov/pubmed/16888102
4) No Author (June 17 2010). New research shows malaria threat is as old as humanity. BBSRC. Retrieved November 24 2010, from http://www.bbsrc.ac.uk/news/health/2010/100617-pr-malaria-old-as-humanity.aspx
5) Dr. B.S. Kakkilaya (No Date). History Of Malaria: Scientific Discoveries. Malaria Site. Retrieved November 24 2010, from http://www.malariasite.com/malaria/history_science.htm
6) No Author (No Date). Malaria. Canada.com. Retrieved November 24 2010, from http://www.bodyandhealth.canada.com/channel_condition_info_details.asp?disease_id=85
7) Malaria: Life Cycle of Plasmodium, Online video. The McGraw-Hill Companies, Inc. No Date. Retrieved November 24 2010, from http://highered.mcgraw-hill.com/olc/dl/120090/bio44.swf
8 ) David J. Weatherall, Louis H. Miller, Dror I. Baruch, Kevin Marsh, Ogobara K. Doumbo, Climent Casals-Pascual, and David J. Roberts (2002). Malaria and the Red Cell. Hematology. Retrieved November 24 2010, from http://www.asheducationbook.hematologylibrary.org/cgi/content/full/2002/1/35
9) Miguel C Fernandez (May 29 2009). Malaria. eMedicine. Retrieved November 24 2020, from http://www.emedicine.medscape.com/article/784065-overview
10) Noa D. Pasternak, Ron Dzikowski (July 2009). PfEMP1: An antigen that plays a key role in the pathogenicity and immune evasion of the malaria parasite Plasmodium falciparum. The International Journal of Biochemistry & Cell Biology, Volume 41 Issue 7, Retrieved December 1 2010, from http://www.sciencedirect.com/science
11) William Trager (June 2005). What triggers the gametocyte pathway in Plasmodium falciparum? Trends in Parasitology, Volume 21 Issue 6. Retrieved December 1 2010, from http://www.cell.com/trends/parasitology/fulltext/S1471-4922(05)00098-X
12) Ernst Hempelmann (November 2006). Hemozoin Biochrstallization in Plasmodium falciparum and the antimalarial activity of crystallization inhibitors. Parasitology Research. Retrieved December 1 2010, from http://parasitology.informatik.uni-wuerzburg.de/login/n/h/j_436-100-4-2006-11-17-313.html
