Tuesday, August 12, 2008


Malaria Protozoans
A microscopic image shows protozoans of the genus Plasmodium, which invade red blood cells and cause malaria in humans. The protozoans are transmitted through the bite of mosquitoes, primarily in tropical and subtropical areas of the world. Malaria is characterized by chills, fever, and sweats. In some cases it can lead to death.
Malaria, debilitating infectious disease characterized by chills, shaking, and periodic bouts of intense fever. Caused by single-celled protozoan parasites of the genus Plasmodium, malaria is transmitted from person to person by the bite of female mosquitoes.
Erythrocytes, or red blood cells, are the primary carriers of oxygen to the cells and tissues of the body. Malaria parasites enter red blood cells in an infected person’s bloodstream and multiply there, eventually causing the cells to burst. The destruction of the red blood cells causes the episodes of chills and fever characteristic of malaria.
Although malaria was once widespread in North America and other temperate regions, the last major outbreak of malaria in North America occurred in the 1880s. The disease today occurs mostly in tropical and subtropical countries, particularly sub-Saharan Africa and Southeast Asia. According to the World Health Organization, malaria is prevalent in over 100 countries. Each year more than 300 million cases of malaria are diagnosed, and more than 1.5 million die of the disease. In recent years, malaria has become more difficult to control and treat because malaria parasites have become resistant to drugs, and mosquitoes that transmit the disease have become resistant to insecticides.Malaria in humans is caused by four species of Plasmodium parasites. Plasmodium falciparum is the most common species in tropical areas and is transmitted primarily during the rainy season. This species is the most dangerous, accounting for half of all clinical cases of malaria and 90 percent of deaths from the disease. Plasmodium vivax is the most widely distributed parasite, existing in temperate as well as tropical climates. Plasmodium malariae can also be found in temperate and tropical climates but is less common than Plasmodium vivax. Plasmodium ovale is a relatively rare parasite, restricted to tropical climates and found primarily in eastern Africa.II.MALARIA LIFE CYCLE
Life Cycle of the Malaria Parasite
Malaria is an infectious disease caused by a one-celled parasite known as Plasmodium. The parasite is transmitted to humans by the bite of the female Anopheles mosquito. The Plasmodium parasite spends its life cycle partly in humans and partly in mosquitoes. (A) Mosquito infected with the malaria parasite bites human, passing cells called sporozoites into the human’s bloodstream. (B) Sporozoites travel to the liver. Each sporozoite undergoes asexual reproduction, in which its nucleus splits to form two new cells, called merozoites. (C) Merozoites enter the bloodstream and infect red blood cells. (D) In red blood cells, merozoites grow and divide to produce more merozoites, eventually causing the red blood cells to rupture. Some of the newly released merozoites go on to infect other red blood cells. (E) Some merozoites develop into sex cells known as male and female gametocytes. (F) Another mosquito bites the infected human, ingesting the gametocytes. (G) In the mosquito’s stomach, the gametocytes mature. Male and female gametocytes undergo sexual reproduction, uniting to form a zygote. The zygote multiplies to form sporozoites, which travel to the mosquito’s salivary glands. (H) If this mosquito bites another human, the cycle begins again.
Plasmodium parasites undergo many stages of development, and their complete life cycle occurs in both humans and mosquitoes. The parasites are transmitted to humans by female mosquitoes of the genus Anopheles. About 60 of the 390 species of Anopheles mosquito transmit the malaria parasite. Of these, only a dozen species are important in the transmission of malaria worldwide. Usually just one or two species play a role in malaria transmission in a particular region where the disease is prevalent.
Female Mosquito Sucking Blood
There are approximately 2,000 species of mosquitoes ranging from the tropics to the Arctic Circle and from sea level to mountaintops. Female mosquitoes have hypodermic mouthparts which enable them to pierce the skin and suck the blood of mammals, birds, reptiles, and other arthropods. Female mosquitoes of the genus Anopheles are responsible for transmitting the malaria parasite from person to person.
Malaria transmission begins when a female mosquito bites a human already infected with the malaria parasite. The mosquito ingests blood containing immature male and female gametes (sex cells) of the malaria parasite. Inside the mosquito’s stomach, the gametes quickly mature. A male gamete fuses with a female gamete to produce a cell known as a zygote. The zygote enters the wall of the mosquito’s gut and develops into an oocyst. The oocyst multiplies to produce thousands of cells known as sporozoites. The sporozoites leave the wall of the gut and migrate to the mosquito’s salivary glands. The mosquito phase of the malaria parasite’s life cycle is normally completed in 10 to 14 days. This development process occurs more slowly in areas with cooler temperatures. Sporozoite development of Plasmodium falciparum is slowed particularly by low temperatures, preventing transmission of this parasite in temperate climates except during summer.When the infected mosquito bites another human, sporozoites in the mosquito’s saliva transfer to the blood of the human. Sporozoites travel in the blood to the liver. In liver cells over the course of one to two weeks, the sporozoites divide repeatedly to form 30,000 to 40,000 merozoites. The merozoites leave the liver to enter the bloodstream, where they invade red blood cells. Inside these blood cells, the merozoites multiply rapidly until they force the red cells to burst, releasing into the bloodstream a new generation of merozoites that go on to infect other red blood cells. Some merozoites divide to form gametocytes, immature male and female gametes. If another mosquito bites the human and ingests these gametocytes, the life cycle of the malaria parasite begins again.III.SYMPTOMS
The fever that characterizes malaria develops when merozoites invade and destroy red blood cells. The destruction of red blood cells spills wastes, toxins, and other debris into the blood. The body responds by producing fever, an immune response that speeds up other immune defenses to fight the foreign invaders in the blood. The fever usually occurs in intermittent episodes. An episode begins with sudden, violent chills, soon followed by an intense fever and then profuse sweating that brings the patient’s temperature down again. Upon initial infection with the malaria parasite, the episodes of fever frequently last 12 hours and usually leave an individual exhausted and bedridden. Repeated infections with the malaria parasite can lead to severe anemia, a decrease in the concentration of red blood cells in the bloodstream. The malaria parasite consumes or renders unusable the proteins and other vital components of the patient’s red cells. The pattern of intermittent fever and other symptoms in malaria varies depending on which species of Plasmodium is responsible for the infection. Infections caused by Plasmodium falciparum, Plasmodium vivax, and Plasmodium ovale typically produce fever approximately every 48 hours, or every first and third day. Infections caused by Plasmodium malariae produce fever every 72 hours, or every fourth day.Infections caused by Plasmodium falciparum are marked by their severity and high fatality rate. This type of malaria can also cause severe headaches, convulsions, and delirium. The infection sometimes develops into cerebral malaria, in which red blood cells infected with parasites attach to tiny blood vessels in the brain, causing inflammation and blocking the flow of blood and oxygen. In Plasmodium vivax and Plasmodium ovale infections, some merozoites can remain dormant in the liver for three months to five years. These merozoites periodically enter the bloodstream, triggering malaria relapses.A.Diagnosis and Treatment
Cinchona Tree
The bark of the cinchona tree, native to South America, contains quinine alkaloids used to treat malaria. The ancient Incas used cinchona bark to treat fevers, and Spanish Jesuit missionaries brought the bark to Europe as a malaria treatment in 1638.
Malaria is difficult to diagnose based on symptoms alone. This is because the intermittent fever and other symptoms can be quite variable and could be caused by other illnesses. A diagnosis of malaria is usually made by examining a sample of the patient’s blood under the microscope to detect malaria parasites in red blood cells. The different species of Plasmodium can be distinguished by their appearance under the microscope. Parasites can be difficult to detect in the early stages of malaria, in cases of chronic infections, or in Plasmodium falciparum infections because often in these cases, not many parasites are present. Recent advances have made it possible to detect proteins or genetic material of Plasmodium parasites in a patient’s blood.Malaria is treated with drugs that block the growth of the Plasmodium parasite but do not harm the patient. Some drugs interfere with the parasite’s metabolism of food, while others prevent the parasite from reproducing. Drugs that interfere with the parasite’s metabolism are related to quinine, the first known antimalarial drug. Quinine is a chemical derived from the bark of the South American cinchona tree and was used as a fever remedy by the ancient Inca in the 15th century. This drug has a bitter taste and produces severe side effects, such as nausea, headache, ringing in the ears, temporary hearing loss, and blurred vision, and large doses can be fatal. However, quinine is still sometimes used in treating malaria today, particularly in developing nations, because it is inexpensive and effective.Chloroquine is a synthetic chemical similar to quinine. It became the drug of choice for malaria when it was developed in the 1940s because it was effective, easy to manufacture, and lacked most of the side effects of quinine. However, in the last few decades, malaria parasites in many areas have become resistant to chloroquine. Presently, it is effective against malaria only in some parts of Central America and the Middle East. Mefloquine is another drug related to quinine that is still largely effective, but for many people, especially those living in developing nations, it is too expensive to use routinely.The other important class of antimalarial drugs depends on a unique aspect of Plasmodium biology. In order to copy its genetic material and reproduce, the malaria parasite must obtain compounds similar to the vitamin folic acid from its human host. Antifolate drugs, which prevent the parasites from properly metabolizing these compounds, inhibit the reproduction of the parasites. In recent years the parasites have developed resistance that diminishes the effectiveness of antifolate drugs when used individually. These drugs can still be effective when given in combination with each other or with other types of antimalarial drugs, because an individual malaria parasite is not likely to be resistant to multiple drugs. Combination drugs are very expensive, however, and are only used in particularly severe cases of malaria.B.Immunity
Sickled Red Blood Cells
A mutation in the gene responsible for producing the oxygen-carrying hemoglobin in the blood causes a disease known as sickle-cell anemia. In this disease the structure of hemoglobin in the human bloodstream is severely altered. The mutation changes the structure of red blood cells to a slender sickle shape. Individuals who inherit two hemoglobin genes with the sickle-cell mutation become ill and often die prematurely, but those who inherit only one gene with the mutation are resistant to malaria.
After repeated infections, people who live in regions where malaria is prevalent develop a limited immunity to the disease. This partial protection does not prevent people from developing malaria again, but does protect them against the most serious effects of the infection. These individuals develop a mild form of the disease that does not last very long and is unlikely to be fatal. Most of the deaths and severe illnesses caused by malaria occur in infants, children, and pregnant women. Infants and children are vulnerable because they have had fewer infections and have not yet built up immunity to the parasite. Pregnant women are more susceptible to malaria because the immune system is somewhat suppressed during pregnancy. In addition, the malaria parasite uses a specific molecule to attach to the tiny blood vessels of the placenta, the tissue that nourishes the fetus and links it to the mother. After exposure to this molecule during her first pregnancy, a woman’s immune system learns to recognize and fight against the molecule. This phenomenon makes a woman particularly vulnerable to malaria during her first pregnancy, and somewhat less susceptible during
Geographic Distribution of the Sickle-Cell Mutation
The genetic mutation to the hemoglobin gene that causes sickle-cell anemia is most widespread in parts of Africa where malaria is prevalent. Individuals who carry one copy of the mutation are less susceptible to malaria than people with two normal hemoglobin genes.
Some people have genetic traits that help them resist malaria by preventing the parasites from growing and developing normally, even in people who are infected with malaria for the first time. Sickle-cell anemia and thalassemia are two inherited blood diseases linked to malaria resistance. People with two sickle-cell or thalassemia genes become seriously ill and often die in childhood if their disease is untreated. But people who have only one sickle-cell or thalassemia gene do not develop the genetic disorder and are, in fact, resistant to malaria. Various sickle-cell or thalassemia genes are widespread among people in Africa, the Mediterranean region, the Middle East, India, and Southeast Asia. Another genetic condition that results in an increased resistance to malaria is ovalocytosis. In ovalocytosis, a protein found in the membrane of red blood cells is abnormal, causing these cells to have an oval shape. This trait, which is common in Southeast Asia and the Pacific Islands, causes chronic anemia but protects people from developing cerebral malaria. Finally, Plasmodium vivax cannot infect people whose red cells lack the Duffy antigen, a protein that is usually found on the surface of red cells. This trait, known as Duffy negativity, is common in people of African ancestry and causes no apparent health problems.C.Prevention and Control
Malaria can be prevented by two strategies: eliminating existing infections that serve as a source of transmission, or eliminating people’s exposure to mosquitoes. Eliminating the source of infection requires aggressive treatment of people who have malaria to cure these infections, as well as continuous surveillance to diagnose and treat new cases promptly. This approach has been successful in areas such as North America and Europe where malaria is not common. However, it is not practical in the developing nations of Africa and Southeast Asia, where malaria is prevalent and governments cannot afford expensive surveillance and treatment programs. Eliminating exposure to mosquitoes, the second strategy, can be accomplished by several means. These means include permanently destroying bodies of stagnant water where mosquitoes lay their eggs; treating such habitats with insecticides to kill mosquito larvae; fogging or spraying insecticides to kill adult mosquitoes; or using mosquito netting or protective clothing to prevent contact with mosquitoes. In 1947 the United States initiated a program to eliminate exposure to malaria-carrying mosquitoes. The program involved applying the insecticide DDT to the interior walls of homes, where female mosquitoes typically rest after feeding. Within five years, this program virtually eliminated illness and death due to malaria in the United States.In 1950 the World Health Organization (WHO) adopted a similar indoor spraying program with the goal of eradicating malaria worldwide within eight years. However, budget considerations limited preliminary research, and the program did not take into account the complex differences in the patterns of malaria transmission in different parts of the world. The eradication program was very successful in some countries, particularly island nations such as Sri Lanka, but in other countries, it did not lead to a significant or sustained reduction of malaria cases.By 1969 it had become clear that eradicating malaria altogether was out of reach, and WHO shifted its focus to malaria control. However, financial obstacles continued to limit the success of this effort. Many of the countries where malaria is prevalent are developing nations where even basic health care is unaffordable for many people and governments lack funds for public health programs. Some countries that had been willing to make short-term financial commitments for malaria eradication programs were unable to make the long-term commitments necessary to sustain malaria control programs. A shortage of health care workers trained in malaria surveillance and control further complicated the problem.During the mid-1960s, insecticide-resistant mosquitoes began to emerge in some regions. Around the same time, malaria parasites developed resistance to chloroquine and other antimalarial drugs. By the late 1970s, malaria had reemerged in many countries, such as Sri Lanka and Mozambique, where eradication programs had virtually eliminated the disease just a few years before. This resurgence was particularly devastating because many people had not been exposed to the disease in years and no longer had protective immunity.Today continuing difficulties with insecticide-resistant mosquitoes and drug-resistant parasites have led to the abandonment of community-wide mosquito control programs in many countries. In these areas, the primary means of preventing malaria is the use of insecticide-treated bed nets. Recent research has shown that these nets are one of the most effective malaria prevention strategies available, but even their modest cost is beyond the means of many families in developing nations. Lack of access to medical care and to effective antimalarial drugs is also a problem in these countries.The resurgence of malaria and the widespread problems of drug and insecticide resistance have focused increasing attention on the need for a malaria vaccine. Developing such a vaccine has been difficult because the malaria parasite has hundreds of different strategies for evading the human immune system. Many of these strategies are not well understood, and it is difficult to develop a vaccine that will block all of the parasite’s ways of getting past the immune system. To be successful, a vaccine will also need to target several different stages of the parasite’s life cycle. Some pharmaceutical companies have been reluctant to work on a malaria vaccine because malaria is most prevalent in developing nations and the companies fear that sales of the vaccine may not be able to recoup the costs of its development. Progress has also been slow because the malaria parasite is difficult to raise in the laboratory and study, since it must live inside the cells of another organism. Despite these hurdles, scientists have developed several possible vaccines that are now being tested in humans.

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