Malaria parasites have been with us since the dawn of time. They probably originated in Africa (along with mankind) and fossils of mosquitoes up to 30 million years old show that the vector for malaria was present well before the earliest history.
From their origins in Africa, P.vivax and P.malariae were possibly brought to the New World by early trans-Pacific voyagers, and this trend for imported malaria continues to this day. P.falciparum may have come in consignments of slaves bound for the Spanish colonies. The Plasmodium parasites are highly specific, with man as the only vertebrate host and Anopheles mosquitoes as the vectors . This specificity of the parasites also points towards a long and adaptive relationship with our species.
Hippocrates was the first to describe the manifestations of the disease, and relate them to the time of year and to where the patients lived - before this, the supernatural was blamed. The association with stagnant waters (breeding grounds for Anopheles) led the Romans to begin drainage programs, the first intervention against malaria. The first recorded treatment dates back to 1600, where the bitter bark of the cinchona tree in Peru was used by the native Peruvian Indians. By 1649, the bark was available in England, as 'jesuits powder' so that those suffering from 'agues' might benefit from the quinine it contained. Malaria in the UK (known as agues) would have been clustered around stagnant marshes, and the invading Roman soldiers would certainly have brought the disease with them. There have been no recent cases due to an infective mosquito bite received within the UK so this is certainly not an endemic region.
Not until 1889 was the protozoal cause of malaria elicited by Laveran working in Algeria, and only in 1897 was the Anopheles mosquito demonstrated to be the vector for the disease. At this point the major features of the epidemiology of malaria seemed clear, and control measures started to be implemented.
The discovery of the insecticide DDT in 1942 and its first use in Italy in 1944 made the ideal of global eradication of malaria seem possible. Subsequently, widespread systematic control measures such as spraying with DDT, coating marshes with paraffin (to block Anopheles mosquito larvae spiracles), draining stagnant water, and the widespread use of nets and cheap, effective drugs such as chloroquine were implemented - with impressive results.
Despite initial success, there was a complete failure to eradicate malaria in many countries due to a number of factors. Although technical difficulties such as vector and parasite drug resistance have played a part, the main failure to reduce the disease is probably due to social, and political factors preventing efficient application of control measures. The malaria control operation was criticised for being too much like a military operation, and the lack of explanations offered to the local populations meant that the control measures received little support or even downright opposition .
Thoughtless man-made irrigation schemes and dams provided new habitats for Anopheles, and resulted in 'man-made' malaria. The extension of urban areas lead to epidemics in the peripheries of the growing cities. Mass migrations of non-immune populations into endemic areas for political reasons further complicates matters. Africa, where the majority of malarial disease is manifest was not even included in the global control mechanism, as it had insufficient infrastructure to support the policy. Despite the setbacks, up until 1969, when the global eradication policy was finally abandoned, the following European countries had managed to completely eradicate their endemic malaria by interrupting transmission: Hungary, Bulgaria, Romania, Yugoslavia, Spain, Poland, Italy, Netherlands, Portugal.
From the early 1970's the malaria situation has slowly and progressively deteriorated, and reduced control measures between 1972 and 1976 due to financial constraints lead to a massive 2-3 fold increases in cases globally. Spraying never truly eradicated the mosquitoes anywhere, and the reduction in the more persistent P.vivax infections were much less than for P.falciparum - though the latter returned in much greater strength as control measures waned. The growing interchange of populations between malarious countries and malaria free countries is responsible for the continuous increase in the number of imported malaria cases in European countries, and causes serious concern because of possible epidemic focal resurgence in receptive areas such as the Mediterranean. Since 1976, several new pockets of malaria transmission have evolved, and a WHO 1980 report recommended that countries which had become non-malarious should maintain at least one malaria vigilance unit.
At present, at least 300,000,000 people are affected by malaria globally, and there are between 1,000,000 and 1,500,000 malaria deaths per year . Malaria is generally endemic in the tropics, with extensions into the subtropics. Malaria in travellers arriving by air is now an important cause of death in non malarious areas , and this is not helped by the common ignorance or indifference of travellers to prophylaxis . Distribution varies greatly from country to country, and within the counties themselves, as the flight range of the vector from a suitable habitat is fortunately limited to a maximum of 2 miles, not taking account of prevailing wind etc. The map indicates current distribution of indigenous malaria according to WHO:
In 1990, 80% of cases were in Africa, with the remainder clustered in nine countries: India, Brazil, Afghanistan, Sri-Lanka, Thailand, Indonesia, Vietnam, Cambodia and China. Current data for Africa is unavailable. The disease is endemic in 91 countries currently, with small pockets of transmission in a further eight. P.falciparum is the predominant species, with 120,000,000 new cases and up to 1,000,000 deaths per year globally. It is the P.falciparum species which has given rise to the formidable drug resistant strains emerging in Asia. In 1989, WHO declared malaria control to be a global priority due to the worsening situation, and in 1993, the World Health Assembly urged member states and WHO to increase control efforts.
In Africa, malaria accounts for up to a third of all hospital admissions, and up to a quarter of all deaths of children under the age of 5. There are up to 800,000 infantile mortalities and a substantial number of miscarriages and very low birth weight (VLBW) babies per year due to the disease. The cost of malaria in economic terms is also high; treatment ranges in cost between $US 0.80 and $US 5.30 depending on local drug resistance, and the total cost in Africa is $US1,800,000,000 per year . A bout of malaria typically costs 10 working days, adding to the economic burden. In Africa it is estimated that an individual receives 40-120 infective mosquito bites per year, compared to only 2 per year in India . Bearing the figures for Africa in mind, it seems incredible that in 1969, global eradication was envisaged from a policy which effectively ignored Africa other than for a couple of pilot schemes.
Biology of Plasmodium Parasites and Anopheles Mosquitos:
The Plasmodium genus of protozoal parasites (mainly P.falciparum, P.vivax, P.ovale, and P.malariae) have a life cycle which is split between a vertebrate host and an insect vector. The Plasmodium species, with the exception of P.malariae (which may affect the higher primates) are exclusively parasites of man. The mosquito is always the vector, and is always an Anopheline mosquito, although, out of the 380 species of Anopheline mosquito, only 60 can transmit malaria. Only female mosquitos are involved as the males do not feed on blood. The basic life cycle of the parasite is shown below:
The
sporozoites from the mosquito salivary gland are injected into the human as the mosquito must inject anticoagulant saliva to ensure an even flowing meal. Once in the human bloodstream, the sporozoites arrive in the liver and penetrate hepatocytes, where they remain for 9-16 days, multiplying within the cells. On release, they return to the blood and penetrate red blood cells in which they produce either
merozoites or
micro and
macrogametocytes, which have no further activity within the human host. Another mosquito arriving to feed on the blood may suck up these gametocytes into its gut, where exflagellation of microgametocytes occurs, and the macrogametocytes are fertilized. The resulting
ookinete penetrates the wall of a cell in the midgut, where it develops into an
oocyst. Sporogeny within the oocyst produces many sporozoites and, when the oocyst ruptures, the sporozoites migrate to the salivary gland, for injection into another host.
This highly specialised life cycle requires specialised biology on the part of the Plasmodium species. The reason that not all mosquitos are vectors for Plasmodium parasites is that refractory mosquitos posses substances toxic to Plasmodium within their cells. A higher trypsin-like activity was also found in the midgut of resistant species , possibly inhibiting ookinete development. Plasmodium parasites seem capable of adapting to any suitable anopheline mosquito, given sufficient time and contact . Sporogeny within the mosquito is governed by environmental temperature as Anopheline mosquitos are poikilotherms.
Once injected into the human host, all Plasmodium species will penetrate hepatocytes. However, P.falciparum and P.malariae sporozoites trigger immediate schizogony whereas P.ovale and P.vivax sporozoites may either trigger immediate schizogony or have a delayed trigger, resulting in dormant hypnozoites. Some strains, such as the North Korean strain, seem to consist of sporozoites with universally delayed triggers, so they all form long lasting hypnozoites. P.vivax may have an incubation period of up to 10 months. Gametocytes produced in the primary attack seem to contain all the genetic information required to create sporozoites of several different activation times. The same seems true for gametocytes produced in relapses where the hypnozoites become activated.
Sexual development of Plasmodium begins as the merozoites invade the erythrocytes after their release from the liver. Within the erythrocyte, shizogony occurs to produce either more merozoites (taking 22 1/2 hours in the case of P.berghei), or the sexual micro and macrogametocytes (taking 26 hours) . In P.falciparum, erythrocytic schizogony takes 48 hours and gametocytosis takes 10-12 days. Normally a variable number of cycles of asexual erythrocytiic shizogony occurs before any gametocytes are produced . The immune system may produce antibodies to the gametocytes at this stage.
Once drawn into the mosquito, the gametocytes increase in volume and escape the erythrocyte. Microgametes are formed by 3 mitotic divisions within the microgametocyte, and are expelled explosively. No further changes affect the female macrogametocyte until fertilisation where the plasmalemmas of male and female gametes fuse and the nucleus of the microgamete enters the female cytoplasm . After fertilisation, the zygote is a motionless globular cell, but after 18 to 24 hours it becomes elongated and motile, containing micronemes and a pellicle. The cell invades the microvillus border, passes through the midgut cells, and lies beneath the basement membrane . The ookinete then becomes a static oocyst, between the basal lamina and the basement cell membrane, and bounded by a thick plasmalemma. The chief source of nutrients is the haemolymph in which the oocyst develops. Sporoblasts form, and sporozoites bud off.
After the cyst ruptures, the sporozoites escape into the haemocoele and migrate to and penetrate salivary gland cells where they lie in vacuoles for up to 59 days. These sporozoites develop and become up to 1000 times more infective than when in the oocyst . They are more antigenic, and bear circumsporozoite polypeptide on their plasmalemma. Sporozoite motility is involved in their invasion of cells and escape from the salivary gland. The sporozoites are about 12µm long and 1µm across, with a single nucleus, anterior to which lie micronemes, and posterior to which lies ER and mitochondria .They posses a complex pellicle, which is responsible for motility, and contains circumsporozoite protein. The apical penetrating region contains extensions of the microneme ducts which release an agent which interacts with host cell plasma membrane during penetration.
A biting mosquito transfers about 10% of its sporozoite load into the capillaries or perivascular tissue. Now the sporozoites must begin their evasion of the host defences, possibly by binding serum proteins for 'camouflage' .Some are destroyed by macrophages, or by antigen specific antibodies in immune individuals, but in non immune individuals, they reach the hepatocytes and initiate schizogeny or become hypnozoites depending on their delay trigger. All sporozoites have left peripheral circulation within 45 minutes ..
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