Today, April 25th 2009, is World Malaria Day. Malaria has probably been killing humans since ancient times. It is documented to have changed the course of history and the outcome of battles. At one time malaria was present in the southern parts of Europe, but is now found mostly in countries in the tropical zone. The present day effects of malaria are also too real, and has an impact on economies that are least able to absorb the blow. According to a WHO document, in 2000, if malaria had been eradicated from Africa 35 years ago the economy of Africa would be improved by $100 billion dollars annually (with an annual GDP of $300 billion, this is a big impact). For the extremely poor countries of Africa this would make a huge difference in quality of life. According to the World Health Organization, In 2005 Malaria killed more than 850,000 children – triple the amount of children AIDS kills. Overall, Malaria is estimated to kill between 1.5 and 2.7 million people annually (this is a slightly higher than the estimate given for AIDS relateddeaths).

History

The earliest textual evidence of the existence of a disease that is probably malaria can be found in ancient texts of China and Egypt as well as classical Greece. In Egypt, the Ebers papyrus dating back to 1550 BC recommends the use of Balantine oil, which protects against mosquito bites to prevent a disease symptoms that sound very much like malaria. The chinese text Shennong Bencao Jing dating back 1500 years recommends the use of wormwood (Artemisia) for treating the symptoms of malaria.

Malaria has affected the outcome of important historical battles, including the Athenian siege of Syracuse in 415 BC. The Athenians were told by spies that a coup by a pro-Athenian faction was imminent in Syracuse and that they should wait in the marshland surrounding the city. As it turns out the Athenian army got malaria and most of the soldiers were killed or sickened. The Syracuse army defeated the Athenians and eventually with the eventual defeat of Sparta this led to the fall of Greece culture and the rise of the Rome (which thanks to being on hills was formed as a malaria free meeting place for the Latins, Sabines, and Etruscans). Interestingly this almost happened again in the same area in WWI when allied forces were in the Syracuse area, however knowledge about how malaria is spread prevented many soldiers from falling ill and only 13 soldiers were died from it. Malaria (cerebral) may also have taken the lives of important historical figures including Alexander the Great (although some scholars dispute this and suggest typhoid fever, poisoning or encephalitis).

Treatment, resistance, and vaccination

The first effective treatment to be prescribed for malaria was probably Artemisia in ancient China, however this did not fall into widespread use over the rest of the world. In its natural form it is not very soluble, and this may have created problems for its distribution. In the early 1600's a Jesuit priest
Agostino Salumbrino in Peru saw the natives using the bark from the Cinchona tree to treat patients with fever and chills (aside from a few pockets of it, malaria was not very endemic to South America pre-Columbus so it is felt the natives had no idea it was malaria they were treating). Agostino suspected this may be effective in treating malaria, and sent a sample to Europe. There, it was confirmed that the treatment was effective in treating malaria. This made the Cinchona tree bark a very valuable
commodity and was nearly driven to extinction, until the well guarded seeds were smuggled out of Peru by the Dutch who successfully cultivated it in Indonesia. The advent of WWI resulted in an acute shortage of quinine, and sparked a desperate the search for synthetic versions. As a result, today we have synthetic versions that are available cheaply. Unfortunately, resistance to quinine has become a problem, but fortunately 3 day therapy with artemisin with the drug mefloquine is still quite effective in curing 95% resistant cases due to the low probability of mutations that can protect against both. Both artemisin (which targest the protein PfATP6) and quinine derivates work by inhibiting the production of hemozoin, which is a unique pigment that is present in the parasite because it needs to break down a redox active molecule heme (ferriprotoporphyrinIX). This makes it an attractive target. The parasite also needs to manufacture its own folates, so anti folates that interfere with folate matabolism are also possible treatments. The treatments we have against malaria are not entirely understood for a mechanism standpoint. However we do know that the parasite only needs a few mutations in the right location to become resistant. Research has been done to create multi-target hybrid drugs which may offer hope in overcoming resistance. For example, John Walsh and Angus Bell at Trinity College have created a “hybrid drug” for malaria that basically links artemisinin and quinine into one drug. Of course there may be strains of malaria resistant to the artemisinin – quinine hybrid because of patients who may have had to face both drugs sequentially. Resistance to being treated one drug at a time means the drug target can evolve just by getting lucky with a right mutation, but if multiple mutations are simultaneously required, the chance of evolution is exponentially reduced. If they can devise a drugs that can attack multiple mechanisms simultaneously it can make the chance of a resistant strain emerging to near zero. It appears the parasite uses a variety of methods to evade antimalarial drugs, for example the mechanism of resistance to chloroquine is unclear but it is likely carried out by a protein known as PfCRT which is believed to either directly transports the chloroquine outside of the digestive vacuole of the parasite where it can't do any damage, or it changes pH balance within the digestive vacuole. PfMDR1 is another protein that has been identified to assist in multi drug resistance. Malaria immunity does not last long within the body, it is known that some people living in areas endemic to malaria and may have a chronic malaria infection with milder strains display immunity, however this immunity disappears within about five years if the person is removed from the environment. There are also a number of attempts to create a malaria vaccine. Unfortunately it's it fairly tricky due to the variation of antigens and the fact that parasite goes through stages which change the antigens for targeting. According to the Malaria Vaccine Initiative, which is a global malaria eradication effort started and funded by the Bill Gates foundation (that's the same Bill Gates who created Microsoft), about 40 antigens have been found that may be good vaccine targets. Traditionally, drug companies have not had incentive to develop treatments for tropical diseases due to the lack of financial return on investment. Now however thanks to the Malaria Vaccine Initiative there are a few promising malaria in the drug development pipeline. For example, earlier this month, a company in the US, Sanaria, announced they are entering FDA Phase 1 testing of a vaccine that utilizes a weakened form of the whole malaria parasite. This would be the first serious malaria vaccine candidate to utilize that approach. The company is getting help from Malaria Vaccine Initiative as well.

Parasite

There are four main parasites that cause malaria in humans.

Plasmodium ovale – causes malaria but the symptoms are mild

Plasmodium malariae – long lasting chronic infection that may last a life time ..fevers at 3 day intervals

Plasmodium vivax – a leading cause of benign recurring malaria the symptoms may be strong symptom but rarely fatal. Between 88% to 100% of Africans are immune to this because they do not express “Duffy” which is a receptor on the surface of red blood cells utilized by the parasite.

Plasmodium falciparum – This is the one that is deadly that we should be most concerned about.

Of the four types of human malaria, genetic analysis has shown that Plasmodium falciparum (P. falciparum) is most closely related to the form of malaria in birds and rats, and may have evolved more recently in comparison to the other three (which are related to monkey malaria). Interestingly, people with a sickle cell anemia allele (mostly people of West African descent) are immune to malaria. These gene which offers no other advantage may have spread in the population due to the fact that it improved survival in malaria afflicted regions.

The malaria parasite has a complex life cycle that involves sexual reproduction within the mosquito host and asexual reproduction in the liver of humans. The presence of just one P. falciparum parasite within the liver can cause malaria. The immune system has a difficult time defeating the parasite
because it best can access it only when it is the “sporozoite” (introduced by the mosquito) and merozoite stage (released by liver cells to infect RBCs), because during those stages the malaria is free floating in the blood and not within a cell. The malaria parasite also has mechanisms to overcome an immune response such as hiding within dead liver cells and flooding the host with antigens in a sort of smoke screen, as well as detaching it's surface protein when an antibody attaches to it. Also, it the surface protein that it displays on infected red blood cells to attach to blood vessel walls and prevent them from traveling to the spleen for destruction can have many variants (over 60 have been identified).

Mosquito that spreads it

Anopheles is the mosquito that spreads malaria. The fact that it is a small mosquito that only bites people at night made it hard to prove that mosquitoes were the carriers of malaria. Control of malaria has concentrated on reducing the prevalence of mosquitoes or competitive displacement of Anopheles. The mosquito can be identified by its posture, spotted wings, long palps, and the fact that it's eggs float singly and freely in water (while most other species eggs are clumped together in a raft). Also its larvae lie parallel to the water surface. Initiatives to prevent malaria do not require a lot of funds, and simple practices such as wearing long sleeve clothing when outside at night, using mosquito nets, mosquito spraying, and clearing places outside residences of stagnant water areas (removing discarded tires and buckets) helps. A recent promising approach for controlling malaria is a special insecticide that kills the malaria mosquito in 12 days, which gives the mosquito enough time to breed but kills it right before the malaria parasite has had time to mature so that it can infect persons. Allowing the mosquito enough time to breed greatly reduces the evolutionary pressure for mosquito populations that are resistant to the insecticide to emerge (although it may exert evolutionary pressure to cause the malaria parasite to speed up that stage of its life cycle).

Conclusion

Malaria is a disease that is costing the world a lot, yet can be prevented fairly effectively using simple steps. The production of a vaccine is sorely needed and may go a long way to help reduce the spread of this disease. Considering all the research going into it I believe eventually there will be an effective vaccine against malaria, but it may take two decades. The control of malaria will require a multi pronged strategy that involves developing co-evolution resistant drugs as well as public health initiatives to control mosquitoes and education initiatives that teach people how to reduce their chances of being bitten by Anopheles. It is possible to eradicate malaria and many countries have done so. For example, since the 1950's nearly all cases of malaria in teh United States have been in people who travelled abroad and acquired it. Also, Sri Lanka has had no deaths from malaria in 3 years, and is on the verge of eradication (thanks to a remarkable effort cases have been reduced by an unheard of 99% in 10 years).

References

• Wikipedia: http://en.wikipedia.org/wiki/Malaria and
  http://en.wikipedia.org/wiki/Plasmodium_falciparum
• PG Bray, SA Ward, PM O'Neill Current Topics in Microbiology and Immunology 2005: “Quinolines and Artemisinin: Chemistry, Biology, and History”
• AC Uhlemann, S Krishna Current Topics in Microbiology and Immunology 2005: “Antimalarial drug resistance in Asia: Mechanisms and Assessment”
• AJJ Knell “Malaria: a publication of the tropical programme of the wellcome trust” Oxford, Oxford University Press, 1991
• Robert Sallares “Malaria and Rome: A History of Malaria in Ancient Italy”
  http://books.google.com/books?printsec=frontcover&id=1uomaTvw11IC&output...
  "Evolution-proof Insecticides May Stall Malaria Forever" http://www.sciencedaily.com/releases/2009/04/090406200740.htm
• Malaria Vaccine Initiative http://www.malariavaccine.org
  "Malaria almost eradicated" (Sri Lanka) http://www.dailynews.lk/2009/04/18/news11.asp