Malaria

ByDr. Girish Chandra

 

MALARIA

(Dr. Girish Chandra)

 

            Malaria is one of the most common infectious diseases and an enormous public health problem. The disease is caused by a protozoan parasites of the genus Plasmodium, which is usually referred to as malaria parasites.

            The term malaria originated from the medieval Italian term, mala aria meaning “bad air” and the disease was formerly called marsh fever due to its association with swamps.

            In 1880, a French army doctor working at the military hospital in Algeria named Charles Louis Alphonse Laveran observed malarial parasites for the first time inside the red blood cells of people suffering from malaria. For this and later discoveries, he was awarded the 1907 Nobel Prize for Physiology or Medicine. The protozoan was named Plasmodium by the Italian scientists Ettore Marchiafava and Angelo Celli. A year later, Carlos Finlay, a Cuban doctor treating patients with yellow fever in Havana, first suggested that mosquitoes were transmitting disease to humans. However, it was Sir Ronald Ross working in India who finally proved in 1898 that malaria was transmitted by mosquitoes to birds. He isolated malarial parasites from the salivary glands of mosquitoes that had fed on infected birds. For this work Ross received the 1902 Nobel Prize in Medicine. The findings of Finlay and Ross were confirmed by a medical board headed by Walter Reed in 1900.

 MALARIA PARASITES

             Malaria is caused by protozoan parasites of the genus Plasmodium (Phylum Apicomplexa). In humans malaria is caused by P. falciparum, P. malariae, P. ovale, and P. vivax, the last one is the most common one responsible for about 80 % of all malaria cases. However, P. falciparum is the most deadly one, responsible for about 15% of infections but 90% of deaths. Parasitic Plasmodium species also infect birds, reptiles, monkeys, chimpanzees and rodents. There have been documented human infections with several simian species of malaria, namely P. knowlesi, P. inui, P. cynomolgi, P. simiovale, P. brazilianum, P. schwetzi and P. simium.

 LIFE CYCLE

             The parasite’s primary (definitive) hosts and vectors are female mosquitoes of the Anopheles genus. A mosquito becomes infected when it takes a blood meal from an infected human. Once ingested, the parasite’s gametocytes, taken up along with the blood differentiate into male or female gametes, which fuse to form zygote in the mosquito gut. The zygote is also called ookinete that penetrates the gut lining and produces an oocyst outside the stomach wall. The diploid zygote first undergoes reduction division  and then divides by multiple fission to produce haploid sporozoites inside the oocyst. When the oocyst ruptures, sporozoites are released that migrate through the mosquito’s body to reach salivary glands, where they are ready to infect a new human host when the mosquito bites a healthy man. This type of transmission is occasionally referred to as anterior station transfer. Only female mosquitoes feed on blood, thus males do not transmit the disease..

             Malaria in humans develops via two phases: an exoerythrocytic (hepatic) and an erythrocytic phase. When an infected mosquito pierces a person’s skin to take a blood meal, sporozoites in the mosquito’s saliva enter the bloodstream and migrate to the liver. Within 30 minutes of being introduced into the human host, they infect hepatocytes, multiplying asexually to form schizont for a period of 6–15 days. Once in the liver they produce thousands of cryptozoites and secondary metacryptozoites, which, following rupture of their host cells escape into the blood and infect red blood cells, thus beginning the erythrocytic stage of the life cycle. The parasites escape from the liver undetected by wrapping themselves in the cell membrane of the host liver cell. Within red blood cells the parasites multiply further asexually producing schizont that burst to release about two dozens of merozoites that invade fresh red blood cells. Such cycles continue to occur every 48 hours causing chill and fever at the release of merozoites from RBCs.  

             Some P. vivax and P. ovale sporozoites do not immediately develop into exoerythrocytic merozoites but instead produce hypnozoites that remain dormant for periods ranging 6–12 months to as long as three years. After a period of dormancy, they reactivate and produce merozoites. Hypnozoites are responsible for long incubation and late relapses in these two species of malaria.

             The parasite is protected from attack by the body’s immune system because for most of its life it resides within the liver and blood cells and is hidden from immune surveillance. However, circulating infected blood cells are destroyed in the spleen. To avoid this, P. falciparum produces adhesive proteins on the surface of the infected blood cells, causing the blood cells to stick to the walls of smaller blood vessels, thereby sequestering the parasite from the passage through the general circulation and spleen. This stickiness of RBCs is the main factor that gives rise to hemorrhagic complications associated with falciparum malaria. The smallest branches of the circulatory system can be blocked by the attachment of masses of these infected red blood cells. In cerebral malaria the sequestrated red blood cells can breach the blood brain barrier, leading to coma.

             Although the red blood cell surface adhesive proteins (called PfEMP1 for Plasmodium falciparum erythrocyte membrane protein 1) are exposed to the immune system, they do not serve as good immune targets because of their extreme diversity. There are at least 60 types of  these proteins within a single parasite and perhaps limitless types in general parasite populations. Also, the parasite switches between a broad repertoire of PfEMP1 surface proteins thus staying one step ahead of the pursuing immune system.

 TREATMENT

             The first effective treatment for malaria was the bark of cinchona tree, which contains quinine. This tree grows on the slopes of the Andes, mainly in Peru.

 Treatment with Chloroquine          


Day 1

4 tablets (600mg base) or 10 mg/kg first dose.
2 tablets (300mg base) or 5 mg/kg 6-8 hours later.

Day 2

2 tablets (300mg base) or 5 mg/kg.

Day 3

2 tablets (300mg base) or 5 mg/kg

Next 14 days

Primaquine, 2 tablets (each tablet contains 7.5 mg base daily with food).

 

          Most drugs used in treatment of malaria are active against the parasite stages in blood and include the following:

 Chloroquine

Sulfadoxine-pyrimethamine combination

Mefloquine  

Atovaquone-proguanil  combination

Quinine

Doxycycline

Artemisinin derivatives

             In addition, primaquine is active against the dormant parasite in liver called hypnozoites and hence prevents relapses. Primaquine should not be taken by pregnant women or by people who are deficient in G6PD (glucose-6-phosphate dehydrogenase).

             Mefloquine is an antimalarial agent that acts as a blood schizonticide. It is effective against all species of malaria (P. falciparum, P. vivax, P. malariae and P. ovale). Its exact mechanism of action is not known. Mefloquine is active against the erythrocytic stages of Plasmodium species. However, the drug has no effect against the exoerythrocytic (hepatic) stages of the parasite and mature gametocytes. Mefloquine is effective against malaria parasites resistant to chloroquine and other 4-aminoquinoline derivatives, proguanil, pyrimethamine and pyrimethamine-sulphonamide combinations.

             Malarone (Atovaquone 250 mg plus Proguanil 100 mg), 4 tablets daily for three consecutive days.  This combination therapy is relatively new and appears to be very effective but it is also very expensive. 

             For over 1,500 years Chinese have used leaves from Artemisia annua shrub (sweet wormwood) to treat malaria. However, it is only in the late 1960s that its anti-malarial ingredient, artemisinin was identified and extracted. Today, artemisinin is considered the treatment of choice for uncomplicated falciparum malaria, as prescribed by the World Health Organization in 2001.

BENEFICIAL EFFECTS OF MALARIA

 Sickle-cell disease

             Distribution of malaria.The best-studied influence of the malaria parasite upon the human genome is the blood disease, sickle-cell disease. In sickle-cell disease, there is a mutation in the HBB gene, which encodes the beta globin subunit of haemoglobin. The normal allele encodes a glutamate at position six of the beta globin protein, while the sickle-cell allele encodes a valine. This change from a hydrophilic to a hydrophobic amino acid encourages binding between haemoglobin molecules, with polymerization of haemoglobin deforming red blood cells into a “sickle” shape. Such deformed cells are cleared rapidly from the blood, mainly in the spleen, for destruction and recycling.

             In the merozoite stage of its life cycle the malaria parasite lives inside red blood cells, and its metabolism changes the internal chemistry of the red blood cell. Infected cells normally survive until the parasite reproduces, but if the red cell contains a mixture of sickle and normal haemoglobin, it is likely to become deformed and be destroyed before the daughter parasites emerge. Thus, individuals heterozygous for the mutated allele, known as sickle-cell trait, may have a low and usually unimportant level of anaemia, but also have a greatly reduced chance of serious malaria infection. This is a classic example of heterozygote advantage.

             Individuals homozygous for the mutation have full sickle-cell disease and in traditional societies rarely live beyond adolescence. However, in populations where malaria is endemic, the frequency of sickle-cell genes is around 10%. The existence of four haplotypes of sickle-type hemoglobin suggests that this mutation has emerged independently at least four times in malaria-endemic areas, further demonstrating its evolutionary advantage in such affected regions. There are also other mutations of the HBB gene that produce haemoglobin molecules capable of conferring similar resistance to malaria infection. These mutations produce haemoglobin types HbE and HbC which are common in Southeast Asia and Western Africa, respectively.

Thalassaemias

             Another set of mutations found in the human genome associated with malaria are those causing blood disorders known as thalassaemias. Studies in Sardinia and Papua New Guinea have revealed that the gene frequency of ?-thalassaemias is related to the level of malarial endemicity in a  populations. A study on more than 500 children in Liberia revealed that those suffering with ?-thalassaemia had a 50% decreased chance of getting clinical malaria. Similar studies have found links between gene frequency and malaria endemicity in the ?+ form of ?-thalassaemia. Presumably these genes have also been selected in the course of human evolution with malaria epidemic.

Duffy antigens

             The Duffy antigens are antigens expressed on red blood cells and other cells in the body acting as a chemokine receptors. The expression of Duffy antigens on blood cells is encoded by Fy genes (Fya, Fyb, Fyc etc.). Plasmodium vivax malaria uses the Duffy antigen to enter blood cells. However, it is possible to express no Duffy antigen on red blood cells owing to the absence of Fy genes (Fy-/Fy-). This genotype confers complete resistance to P. vivax infection. The genotype is very rare in European, Asian and American populations, but is found in almost all indigenous population of West and Central Africa. This is thought to be due to high exposure of populations to P. vivax in Africa in the last few thousand years.

 G6PD

             Glucose-6-phosphate dehydrogenase (G6PD) is an enzyme which normally protects from the effects of oxidative stress in red blood cells. However, a genetic deficiency in this enzyme results in increased protection against severe malaria.

 HLA and interleukin-4

             HLA-B53 is associated with low risk of severe malaria. This MHC class I molecule presents liver stage and sporozoite antigens to T-Cells. Interleukin-4 is produced by activated T-cells and promotes proliferation and differentiation of antibody-producing B-cells. A study of the Fulani of Burkina Faso found that the IL4-524 T allele was associated with elevated antibody levels against malaria antigens, which raises the possibility that this might be a factor in increased resistance to malaria.