*This page was created as an assignment for an undergraduate class at Davidson College

Malaria

Malaria is an arbovirus that is vectored (transmitted) to humans by the Anopheles mosquito (Cheong 1965). The largest and most studied genus of mosquito, Anopheles’ found in both tropical and temperate areas around the world (Horsfall 1955) An arbovirus is a vector that replicates in an invertebrate vector and in a vertebrate host (Gullan et al. 2005). Malaria is caused by a parasite of the genus Plasmodium which is ingested by the Anopheles mosquito when it takes a blood meal from an infected human host. There are four major types of malaria-causing Plasmodium, but the P. falciparum variety accounts for 80% of malaria cases and 90% of malaria-related deaths world wide (Wikipedia 2006). Of these fatalities, 85-90% are from sub-Saharan Africa where warm weather allows for year-round transmission of the disease in some areas. Contrary to popular belief, not all mosquito species bite humans and of those that do, only females feed on humans (Buice 1930). Females bite humans because they need the nutritious blood-meal before they lay their eggs (Barnes 2005). Male mosquitoes, however, feed on nectar produced by flowering plants.

After a female Anopheles mosquito takes a blood meal from a malaria-infected host, the Plasmodium parasites travel to the mosquito’s gut where a male and a female Plasmodium fuse to form a single parasite, which burrows into the tissues of the mosquito’s stomach wall (Buice 1930). While in the stomach wall, the fused Plasmodium divides several times producing several identical parasites. The resulting individuals move through the mosquito’s circulatory system and into its salivary glands. This process can take from 1-2 weeks depending on the variety of Plasmodium. Therefore, it takes at least a week after feeding on an infected host for a mosquito to become infectable again.

When an infectable mosquito takes a blood meal from a human host, the Plasmodium is transferred, along with an anesthetic, into the host’s wound. The anesthetic serves to numb nerves in the bite area so that the feeding mosquito can go unnoticed by the organism it is feeding on, thus lengthening the time the mosquito is able to feed. Studies by Menard et al. (2006) suggest approximately 20 parasites are transferred to into the host’s skin with every bite. These parasites were found to remain in the skin for a substantial amount of time. Around half of the parasites remained in the skin an hour after the initial bite, and parasites continued to be detected in skin tissues up to seven hours after the bite. When the Plasmodium parasites leave the skin they enter the bloodstream where they travel to the liver. It was previously thought that the Plasmodium was only able to develop in the liver, however, Menard and his colleagues have shown that a fraction of the parasites, around 25% are drained into lymphatic vessels where they begin to develop. Parasites that migrated into lymph nodes showed significant degradation four hours after infection, which suggests that they were being destroyed by leukocytes. Menard and his colleagues found that a small portion of these parasites were able to escape the lymph nodes. However, 52 hours after infection, there were no Plasmodium parasites in the lymph nodes. The parasites require more than 52 hours to develop and only fully developed Plasmodium can enter red blood cells. Therefore, parasites that enter the lymph nodes are not believed to contribute to malaria symptoms.

Parasites that enter the bloodstream invade hepatocytes in the liver minutes after infection (Frevert et al. 2006). A study by Frevert et al. showed that the adhesion molecules circumsporozoite protein (CSP) and thrombospondin-related adhesive protein (TRAP) produced by Plasmodium parasites adhere to highly sulfated oligosaccharides in heparan sulfate, found on liver cells, to promote rolling, arrest, and extravasation of the parasites into the liver. To reach hepatocytes, the parasites must traverse a layer of sinusoidal cells which is made up of epithelial and Kupffer cells. Frevert et al. showed that the Plasmodium parasites cross the layer of sinusoidal cells by being transported across Kupffer cells by a process called transcytosis. Transcytosis involves the phagocytosis and subsequent exocytosis of the Plasmodium by the Kupffer cell. For reasons not yet known, vesicles containing the parasites do not fuse with highly acidic endosomes in Kupffer cells. Fusion with theses endosomes would kill the parasite. Furthermore, high concentrations of the CSP protein are secreted into the cytosol by the Plasmodium parasites. Frevert et al. believe that this protein selectively kills the Kupffer cells traversed by the parasites. Otherwise, these cells would become activated phagocytes that would destroy the parasites. Destroying Kupffer cells also prevents them from releasing cytokines that would signal the presence of the parasite and cause an immune response in the form of inflammation and the recruitment of leukocytes to the site of inflammation. This is just one way that the Plasmodium parasite evades the human immune system. Once they are past the sinusoidal cell layer, the parasites invade hepatocytes where they can hide from the body's immune system indefinitely. Part of their ability to hide in liver cells may be due to the low expression of MHC class I molecules on liver cells (Janeway et al. 2005). In the hepatocytes, the Plasmodium parasites multiply asexually with full development taking 6-15 days (Wikipedia 2006).

Developed parasites are released from the liver and enter the bloodstream where they infect red blood cells. The parasites cause the expression of PfEMP1 on the cell’s surface (Cowman et al. 2005). PfEMP1, a protein that is produced by the var gene family, causes red blood cells to adhere to vessel linings. This removes the red blood cell from circulation, preventing it from being destroyed, and thus preventing the destruction of the parasite. The parasites remain in red blood cells for a short period of time, where they produce and secrete a toxin (Buice 1930). Eventually the parasites cause the red blood cell to burst and its contents are released into the bloodstream. All of the infected red blood cells in an infected individual burst at the same time. The large amount of toxin that this releases can cause flu-like symptoms including chills, fatigue, headache, muscle pain, jaundice, nausea, abdominal pain, vomiting and diarrhea within a week or two of infection (Kujtan 2006). The rupturing of red blood cells occurs once every 48 hours causing chills and fever every other day, signature symptoms of malaria.

Although promoting the adherence of red blood cells to vessel walls helps to preserve the Plasmodium parasite, it is still vulnerable to attack and elimination by the circulating leukocytes while in the blood. A study by Cowman et al. (2005) found that P. falciparum uses “cloaking genes” to disguise itself from the immune system. The parasite has 60 var cloaking genes and the promoter for each gene silences the transcription of the other cloaking genes so that only one is produced at a time. The parasite evades the immune system by periodically switching from gene to gene so that the lymphocytes of the immune system are not able to keep up with the changing proteins. It is possible to develop immunological immunity to malaria, however, children do not survive the disease long enough to develop immunity. The gene cloaking mechanism is so effective that a person would have to be exposed to malaria continually for five years to develop immunity. Furthermore, adults in Papua New Guinea who move to mosquito/malaria-free mountainous areas to work, lose their immunity after a short period of time. In addition to cloaking genes, the Plasmodium parasite has been found to hinder adaptive immune responses in its blood stages. A study by Millington et al. (2006) found that dendritic cells isolated from infected animals 12 and 20 days after malaria infection, showed lower levels of activation than those in non-infected animals, and expressed lower levels of CD40, CD80, CD86, and MHC class I and II molecules on their surfaces. This is a significant hindrance to the adaptive immune response because activated dendritic cells are responsible for carrying foreign proteins to the lymph nodes where they are presented in MHC class II complexes to T-cells, which attack the pathogens and activate antibody-producing B-cells. A further hindrance to the immune system is the lack of MHC class I complexes on the surface of red blood cells (Janeway et al. 2005). This prevents their recognition by cytotoxic T-cells that would otherwise destroy the red blood cells along with the parasites inside.

There are several drugs available to treat malaria, the most popular of which is Chloroquine (Wikipedia 2006). However, resistance of P. falciparum to this drug has recently spread from Asia to Africa rendering Chloroquine ineffective in parts of these areas. Many of the drugs used to treat malaria can also be taken in a preventative manner. In this case, the drugs are taken daily or weekly in lower doses than those taken by infected individuals. Malaria vaccines are currently being developed. The pharmaceutical company GlaxoSmithKline have created a vaccine that reduces infection risk by around 30%, and scientist at the University of Edinburgh have discovered an antibody that protects against the disease, but as of now there are no vaccines that are completely effective.

 

References

Barnes E. 2005. Diseases and human evolution. Albuquerque, NM: University of New Mexico Press. p 67-68

Buice AW. 1930. Malaria: A Health Lesson for Upper Grades and High School. Peabody Journal of Education 7(5):285-289

Cheong WH, McWilson W, Omar AH, Mahadevan S. 1965. Anopheles balbacensis balabacensis Identified as vector of simian malaria in Malaysia. Science 150(3701): 1314-1315.

Cowman AF, Crabb B. 2005 December 28. Scientists Lift Malaria’s Cloak of Invisibility. Howard Hughes Medical Institute. <http://www.hhmi.org/news/cowman_crabb20051228.html> Accessed 2006 April 25.

Frevert U et al. 2005. Interaction Between Malaria Sporozoites and Liver Cells. NYU Medical Center: Medical Parasitology. <http://www.med.nyu.edu/parasitology/faculty/ufrevert.html> Accessed 2006 April 25.

Gullan PJ, Cranston PS. 2005. The Insects: an outline of entomology. 3rd ed. Massachusetts: Blackwell Publishing. p 384.

Horsfall, WR. 1955. Mosquitoes: Their bionomics and relation to disease. New York, NY: The Ronald Press Company. p 7.

Janeway C, Travers P, Walport M, Shlomchik M. 2005. Immunobiology: The Immune System in Health and Disease. New York, New York: Garland Science Publishing. p. 23, 80-84.

Kujtan P. no date. What Disease Kills Over a Million People Every Year? <http://www.aresearchguide.com/drkmalaria.html> Accessed 2006 April 25.

Menard R et al. 2006 January 23. Malaria Parasites Develop In Lymph Nodes. Science Daily. <http://www.sciencedaily.com/releases/2006/01/060123074024.htm> Accessed 2006 April 25. Also published online in Nature Medicine, January 22, 2006.

Millington OR, Di Lorenzo C, Phillips SR, Garside P, Brewer, JM. 2006. Suppression of adaptive immunity to heterologous antigens during Plasmodium infection through hemozoin-induced failure of dendritic cell function. Journal of Biology 5:5. <http://jbiol.com/content/5/2/5>

Wikipedia online Encyclopedia. 2006. Malaria. <http://en.wikipedia.org/wiki/Malaria> Accessed 2006 April 25.

 

If you have any questions about this website you can contact me at jolatting@davidson.edu

Return to My Home Page

Return to Davidson College Home Page

Return to the Davidson College Immunology Home Page