Evolution of Malaria Parasites

Man and Malaria seem to have evolved together. It is believed that most, if not all, of today’s populations of human malaria may have had their origin in West Africa (P. falciparum) and West and Central Africa (P. vivax) on the basis of the presence of homozygous alleles for hemoglobin C and RBC Duffy negativity that confer protection against P. falciparum and P. vivax respectively. Recent molecular studies have found evidence that human malaria parasites probably jumped onto humans from the great apes, probably through the bites of vector mosquitoes.

history-parasite250The ancestors of the malaria parasites have probably existed at least half a billion years ago. Molecular genetic evidence strongly suggests that the pre-parasitic ancestor for malaria parasite was a choroplast-containing, free-living protozoan which became adapted to live in the gut of a group of aquatic invertebrates. This single-celled organism probably had obligate sexual reproduction, within the midgut lumen of a host species. At some relatively early stage in their evolution, these “premalaria parasites” acquired an asexual, intracellular form of reproduction called schizogony and with this, the parasites greatly increased their proliferative potential. (This schizogony in the RBCs of humans causes the clinical manifestations of malaria). Among the invertebrates to which the ancestors of the malaria parasites became adapted were probably aquatic insect larvae, including those of early Dipterans, the taxonomic order to which mosquitoes and other blood-sucking flies belong. These insects first appeared around 150 million to 200 million years ago. During or following this period, certain lines of the ancestral malaria parasites achieved two-host life cycles which were adapted to the blood-feeding habits of the insect hosts. In the 150 million years since the appearance of the early Diptera, many different lines of malaria and malaria-like parasites evolved and radiated. The malaria parasites of humans evolved on this line with alternate cycles between human and the blood-feeding female Anopheles mosquito hosts. Fossil mosquitoes have been found in geological strata 30 million years old.[1]

From Great Apes to Man: P. falciparum is found to be very closely related to a malaria parasites of chimpanzees, P. reichenowi and these two are more closely related to the malaria parasites of birds than to those of other mammals. The lineage of these parasites possibly occurred around 130 million years ago, nearly about the same time as the origin of the two-host life cycle involving blood-feeding Dipterans and land vertebrates. The separation of the lines that led to P. falciparum and P. reichenowi probably occurred only 4 million to 10 million years ago, overlapping the period in which the human line diverged from that of the African great apes. Recent phylogenetic analysis indicates that all extant P. falciparum populations originated from P. reichenowi, likely by a single host transfer, occurring as early as 2–3 million years ago, or as recently as 10,000 years ago.[1,2] The modern, lethal strains of P. falciparum probably emerged within the last 5,000– 10,000 years, after agriculture took roots in Africa.[1]

Pg-23-malaria-alamy_458808aP. falciparum probably jumped from Gorillas: Different studies have suggested that P. falciparum malaria probably jumped from great apes to man, probably by a single host transfer by vector mosquitoes. While earlier reports suggested the origin from chimpanzees[2] or bonobos[3], a new study from central Africa points to Gorillas. A single-genome amplification strategy to identify and characterize Plasmodium spp., DNA sequences in nearly 3,000 faecal samples from wild-living apes from field sites throughout central Africa, found Plasmodium infection in chimpanzees (Pan troglodytes) and western gorillas (Gorilla gorilla), but not in eastern gorillas (Gorilla beringei) or bonobos (Pan paniscus). Ape plasmodial infections were highly prevalent, widely distributed and almost always made up of mixed parasite species. Analysis of more than 1,100 mitochondrial, apicoplast and nuclear gene sequences from chimpanzees and gorillas revealed that 99% grouped within one of six host-specific lineages representing distinct Plasmodium species within the subgenus Laverania. One of these from western gorillas comprised parasites that were nearly identical to P. falciparum. In phylogenetic analyses of full-length mitochondrial sequences, human P. falciparum formed a monophyletic lineage within the gorilla parasite radiation. These findings indicate that P. falciparum is of gorilla origin and not of chimpanzee, bonobo or ancient human origin.[4-8]

P. malariae, P. ovale, and P. vivax diverged over 100 million years ago along the lineage of the mammalian malaria parasites. P. ovale is the the sole known surviving representative of its line and causes infection only in humans. P. malariae was a parasite of the ancestor of both humans and African great apes and had the ability to parasitize and cross-infect both host lineages as they diverged around five million years ago. P. malariae is found as a natural parasite of chimpanzees in West Africa and P. brazilianum that infects New World monkeys in Central and South America is morphologically indistinguishable from P. malariae. P. malariae, like P. ovale, is the only confirmed and extant representative of its line. P. vivax, closely related to P. shwetzi, a parasite of African great apes, belongs to a group of malaria parasites like P. cynomolgi, that infect monkeys. The time of divergence of P. vivax from P. cynomolgi is put at 2-3 million years ago.[1] Several cases of P. knowlesi infection, zoonotic from macaque monkeys, have been recently reported from Southeast Asia, including Malaysia, Thailand, Viet Nam, Myanmar and Phillippines.[9-13]

Mosquitoes adapt: End of the last glacial period and warmer global climate heralded the beginnings of agriculture about 10000 years ago. It is argued that the entry of agricultural practice into Africa was pivotal to the subsequent evolution and history of human malaria. The Neolithic agrarian revolution, which is believed to have begun about 8,000 years ago in the “Fertile Crescent,” southern Turkey and northeastern Iraq, reached the western and Central Africa around 4,000 to 5,000 years ago. This led to the adaptations in the Anopheles vectors of human malaria. The human populations in sub-Saharan Africa changed from a low-density and mobile hunting and gathering life-style to communal living in settlements cleared in the tropical forest. This new, man-made environment led to an increase in the numbers and densities of humans on the one hand and generated numerous small water collections close to the human habitations on the other. This led to an increase in the mosquito population and the mosquitoes in turn had large, stable, and accessible sources of blood in the human population, leading to very high anthropophily and great efficiency of the vectors of African malaria. Even though the practice of agriculture had developed throughout the tropics and subtropics of Asia and the Middle East up to several thousand years before those in Africa, simultaneous animal domestication in Asia probably prevented the mosquitoes from developing exclusive anthropophilic habits. In most parts of the world, the anthropophilic index (the probability of a blood meal being on a human) of the vectors of malaria is much less than 50% and often less than 10 to 20%, but in sub-Saharan Africa, it is 80 to almost 100%. This is probably the most important single factor responsible for the stability and intensity of malaria transmission in tropical Africa today.[1]

history-spread250Spread of Malaria: From its origin in the West and Central Africa, malaria spread all across the globe to become the worst killer disease ever suffered by mankind. The parasites spread to other areas through the journey of man, following the human migrations to the Mediterranean, Mesopotamia, the Indian peninsula and South-East Asia.[1] Although P. vivax and P. malariae had achieved the widest global distribution, today P. malariae has lost its predominance and P. vivax and P. falciparum are the most commonly encountered malaria parasites. Almost 85% of the nearly 500 million annual malaria cases occur in sub-Saharan Africa and about 85% of cases in Africa are caused by P. falciparum, the remaining cases being caused by the other three strains. P. vivax is now the most geographically widespread of the human malarias, estimated to account for 100-300 million clinical cases across much of Asia, Central and South America, the Middle East, where 70–90% of the malaria burden is of this species and the rest due to P. falciparum.[1,14] P. malariae causes sporadic infections in Africa, parts of India, western Pacific and South America, whereas P. ovale is restricted to tropical Africa, New Guinea, and the Philippines.[1]

Malaria seems to have been known in China for almost 5,000 years. (Men from ancient China, who traveled to malarious areas were advised to arrange for their wives to be remarried). Sumerian and Egyptian texts dating from 3,500 to 4,000 years ago mention about fevers and splenomegaly suggestive of malaria. (The enlarged spleens of Egyptian mummies are believed to have been caused by malaria). It appears that P. falciparum had reached India by around 3,000 years ago. It is believed that malaria reached the shores of the Mediterranean Sea between 2,500 and 2,000 years ago and northern Europe probably mainly between 1,000 and 500 years ago. The waves of invasions that swept across the continents helped the cause of malaria parasite as well. By the Middle Ages, Kings and feudal lords had the best wetlands under their control, but in turn had to fear marshes as breeding grounds of plagues and incurable fevers (The term ‘paludismo’ comes from the Latin ‘Palus’ for lagoon). A royal decree was passed in 11th-century Valencia sentencing any farmer to death who planted rice too close to villages and towns and the conflict between rice growers and the authorities continued for centuries. The disease continued spread and decimated local populations with the increase in rice farming.

By the beginning of the Christian era, malaria was widespread around the shores of the Mediterranean, in southern Europe, across the Arabian peninsula and in Central, South, and Southeast Asia, China, Manchuria, Korea, and Japan. Malaria probably began to spread into northern Europe in the Dark and Middle Ages via France and Britain. The growth in international trade in the sixteenth century contributed to the spread of disease, as international traders introduced new sources of infection. Europeans and West Africans introduced malaria in the New World at the end of 15th century AD. P. vivax and P. malariae were possibly brought to the New World from South-East Asia by early trans-Pacific voyages. P. falciparum probably reached the Americas through the African slaves brought by the Spanish colonisers of Central America. At first the Caribbean and parts of Central and South America were affected and from the mid-18th century, it spread across the North American continent. Over the next 100 years, malaria spread across the United States of America and Canada and by around 1850 A.D., it prevailed through the length and breadth of the two American continents. At this time, malaria was common in Italy, Greece, London, Versailles, Paris, Washington D.C., and even New York City.

Thus by 19th century, malaria reached its global limits with over one-half of the world’s population at significant risk and 1 in 10 affected expected to die from it. From the time of the voyages of Columbus until the mid-19th century, European trade and colonization in the tropics were marked by enormous losses of life from malaria. On the coasts of West Africa, mortality rates often exceeding 50% of a company per year of contact were the norm. From the mid-19th century onward, with the use of the Cinchona bark, mortality rates fell rapidly to less than one-quarter of this. Up to early 20th century, repeated untreated infections of P. vivax and prolonged infections of P. malariae also contributed significantly to the mortality along with the lethal P. falciparum. Poor living conditions, poverty and famine probably contributed to the high mortality. During the past 100 years, nearly 150 million to 300 million people would have died from the effects of malaria, accounting for 2-5% of all deaths. In the early part of the century, malaria probably accounted for 10% of global deaths to malaria and in India it probably accounted for over half.

By mid 20th century, the mortality started dropping, mainly as a result of the spontaneous decline in contact between human and vector populations as a result of improved living conditions as well as by the vector control measures. By the early 1950s, malaria almost disappeared from North America and from almost all of Europe. However, from the tropics where it is endemic, it can spread across continents through the vectors (mosquitoes) and the hosts (men) carried on the boats, trawlers, ships, jets and surface transport.

Further Reading:

  1. Carter R, Mendis KN. Evolutionary and Historical Aspects of the Burden of Malaria. Clinical Microbiology Reviews. October 2002;15(4):564-594. Full text at http://cmr.asm.org/cgi/content/full/15/4/564
  2. Rich SM, Leendertz FH, Xu G et al. The origin of malignant malaria. PNAS 2009;106:14902-14907. Full Text at http://www.pnas.org/content/early/2009/07/31/0907740106.full.pdf
  3. Krief S et al. On the Diversity of Malaria Parasites in African Apes and the Origin of P. falciparum from Bonobos. PLoS Pathog 2010;6(2): e1000765.[Full Text]
  4. Liu W et al. Origin of the human malaria parasite Plasmodium falciparum in gorillas. Nature. 23 September 2010;467:420–425. doi:10.1038/nature09442. Available at http://www.nature.com/nature/journal/v467/n7314/full/nature09442.html
  5. Holmes EC. Malaria: The gorilla connection. Nature 23 September 2010;467:404–405. doi:10.1038/467404a. Available at http://www.nature.com/nature/journal/v467/n7314/full/467404a.html
  6. Prugnollea F et al. African great apes are natural hosts of multiple related malaria species, including Plasmodium falciparum. PNAS January 19, 2010. 10.1073/pnas.0914440107. Available at http://www.pnas.org/content/early/2010/01/11/0914440107.full.pdf+html
  7. Connor S. Evolution of malaria is traced back to greatest ape: Research may open new avenues of study to halt disease. Available at http://www.independent.co.uk/news/science/evolution-of-malaria-is-traced-back-to-greatest-ape-2087035.html
  8. Alcock K. Cerebral malaria may have passed from gorillas to us. Available at http://www.bbc.co.uk/news/science-environment-11393664
  9. Daneshvar C et al. Clinical and Laboratory Features of Human Plasmodium knowlesi Infection. Clinical Infectious Diseases 2009;49:852–860
  10. Putaporntip C, Hongsrimuang T, Seethamchai S et al. Differential Prevalence of Plasmodium Infections and Cryptic Plasmodium knowlesi Malaria in Humans in Thailand. The Journal of Infectious Diseases 2009;199:1143–1150
  11. Singh B, Sung LK, Radhakrishnan A et al. A large focus of naturally acquired Plasmodium knowlesi infections in human beings. The Lancet 2004;363(9414):1017-1024
  12. Cox-Singh J, Singh B. Knowlesi malaria: newly emergent and of public health importance? Trends in Parasitology. 2008;24(9):406-410.
  13. Peter Van den Eede, Hong Nguyen Van, Chantal Van Overmeir et al. Human Plasmodium knowlesi infections in young children in central Vietnam. Malaria Journal 2009;8:249. Full Text at http://www.malariajournal.com/content/8/1/249
  14. Rich SM, Ayala FJ. Evolutionary Origins of Human Malaria Parasites. In Krishna R. Dronamraju, Paolo Arese (Ed). Emerging Infectious Diseases of the 21st Century: Malaria – Genetic and Evolutionary Aspects. Springer US 2006. pp.125-146.

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