BioMed Research International

BioMed Research International / 2018 / Article
Special Issue

Current Trends in Studies of Ancient Diseases

View this Special Issue

Review Article | Open Access

Volume 2018 |Article ID 8516785 |

Dong Hoon Shin, Min Seo, Jong Ha Hong, Eunju Lee, "Paleopathological Considerations on Malaria Infection in Korea before the 20th Century", BioMed Research International, vol. 2018, Article ID 8516785, 14 pages, 2018.

Paleopathological Considerations on Malaria Infection in Korea before the 20th Century

Academic Editor: Stefano D’Amelio
Received28 Dec 2017
Accepted01 Apr 2018
Published09 May 2018


Malaria, one of the deadliest diseases in human history, still infects many people worldwide. Among the species of the genus Plasmodium, P. vivax is commonly found in temperate-zone countries including South Korea. In this article, we first review the history of malarial infection in Korea by means of studies on Joseon documents and the related scientific data on the evolutionary history of P. vivax in Asia. According to the historical records, malarial infection was not unusual in pre-20th-century Korean society. We also found that certain behaviors of the Joseon people might have affected the host-vector-pathogen relationship, which could explain why malarial infection prevalence was so high in Korea at that time. In our review of genetic studies on P. vivax, we identified substantial geographic differentiation among continents and even between neighboring countries. Based on these, we were able to formulate a strategy for future analysis of ancient Plasmodium strains in Korea.

1. Introduction

Globally, malaria is the fifth deadliest disease, infecting approximately 200 million people worldwide [13]. Malarial infection is mediated by the arthropod vector Anopheles mosquito. The Plasmodium parasite has a complex life-cycle of sexual reproduction inside the mosquito vector and asexual stage in the vertebrate host. In brief, malarial sporozoites are inoculated into human hosts when a mosquito bites them [4]. After a dormant phase, they differentiate into merozoites for release into the bloodstream, upon which they invade erythrocytes (the beginning of asexual multiplication). The bursting of infected red blood cells (RBCs) by merozoite multiplication is responsible for the typical malarial fever [4]. Some of the merozoites then develop into gametocytes, which are taken up by a female mosquito [4]. Sexual reproduction in the anopheline mosquito is followed by sporozoite migration into the salivary gland, from which they are inoculated into a vertebral host, thus beginning a new cycle of malarial infection [4].

In general, five species of genus Plasmodium are known to cause malaria: P. falciparum, P. vivax, P. malariae, P. ovale, and P. knowlesi [5]. Recent malaria outbreak in Brazil has also been traced to new zoonotic transmission of P. simium from monkey [6]. Among them, P. vivax and P. falciparum are the most commonly detected causative pathogens of human malaria. Clinical manifestations of uncomplicated malaria are nonspecific: headache, fever, malaise, myalgia, nausea, vomiting, and abdominal pain. Rare cases of malaria show severe manifestations including anemia, thrombocytopenia, pulmonary edema, renal failure, hepatic dysfunction, and splenic rupture [7].

Although malarial species share typical signs and symptoms such as undulating intermittent fever, they also have different traits depending on each subtype. P. falciparum’s symptoms are serious enough to show the highest mortality rate whereas P. vivax, P. malariae, and P. ovale exhibit generally nonfatal clinical courses [5]. The geographical distribution of each Plasmodia subtype differs as well. P. falciparum is more prevalent in tropical or subtropical zones including Sub-Saharan areas but relatively absent in temperate countries [8]. Meanwhile, P. vivax generally infects human populations in temperate and tropical zones but is not so prevalent in Sub-Saharan Africa [1, 3, 9]. P. vivax malaria was endemic even in some high latitude countries (Finland and Russia, etc.) at certain points in history [4, 10, 11].

As malaria historically has been, and continues to be, one of the most serious diseases, it has attracted the attention of many paleopathologists. Studies on ancient malarial infection have been conducted by various methods such as osteoarchaeological and biomedical approaches [12]. As chronic-stage vivax malaria was generally known to induce anemia, further causing porotic hyperostosis (PO) or cribra orbitalia (CO) in the cranium [10], anthropologists have searched for the presence of PO or CO in skeletal remains as indirect evidences of malarial infection [5, 1215]. Nevertheless, PO or CO has clear limitations with respect to its application to the study of ancient malaria because Plasmodium infection is not the only cause of them [12, 16]. Other pathologies such as inherited hemolytic anemia, scurvy, or malignancies are also known to induce the same skeletal changes of PO or CO [5, 12].

In recent years, the paleopathological study of malaria has been revolutionized by successful applications of immunological and ancient DNA (aDNA) analyses to archaeological specimens. To detect malaria-related proteins, researchers performed the dipstick assay or new-generation immunoassays on ancient mummies[1719] or skeletons [20, 21]. The immunological assay became an effective screening method to secure the evidence of ancient malarial infection [5]. Also, Plasmodium aDNAs reportedly have been obtained from Egyptian mummies [2, 2224], an infant skeleton dating to ancient Rome [25], 15th-to-19th-century infant of Bavaria [26], and 1st-to-2nd-century adult skeletons of Italy [27]. As a paleopathological tool, aDNA analysis is useful for confirming the presence of malarial genomes remnant in archaeological specimens as well as for revealing the origin and dispersal of the protozoan parasite in evolutionary history [28].

Although immunological and molecular analyses have become more reliable tools for the study of ancient malaria, the data obtained to date are not sufficient in terms of quantity and quality [16]. Moreover, since previous studies have focused mainly on ancient Egyptian, Roman, and Renaissance European remains thus far [5], such information as has been obtained from malaria aDNA reflects a serious geographical bias. Extensive geographic sampling is thus necessary in order to understand the demographic history of malaria much more comprehensively and clearly [4, 2931]. Like the other continents, Asia is also a region where malaria has historically been epidemic and endemic. In several Asian countries, many people continue to have suffered from and even died of Plasmodium infection. Nonetheless, most of the requisite paleopathology still remains to be revealed in Asia as few medical studies on the ancient malaria have been reported in the area. Herein, then, we offer this historical review as a fundamental basis for future research of ancient malaria infection in Korea and other Asian countries.

2. Origin and Dispersal of Vivax Malaria Parasite

Parasitologists have speculated that human malaria might have been transmitted from nonhuman primates by a host-switch event [11]. Initially, they presumed that P. falciparum was transmitted from chimpanzees and gorillas in Africa [18] while P. vivax originated from another nonhuman primate, possibly macaques, in Southeast Asia [4, 32, 33]. However, this hypothesis is seriously challenged nowadays by the genetic analysis of malaria worldwide. Alternatively, a recent study revealed that both P. falciparum and P. vivax originated in Africa and that P. vivax transmission to human beings might have occurred much earlier than P. falciparum did by a host switch [34].

According to the estimated time to most recent common ancestor (TMRCA), the ancestor of the extant P. vivax populations existed between 50 and 550 ka before the present [3]. In a demographic history inferred from the P. vivax genome analysis, the global population size of vivax malaria might have expanded slowly until about 60 ka BP, which is closely consistent with the demographic history of mankind [3, 35]. Once the divergence of African and Eurasian P. vivax populations occurred at about 51 ka BP, the latter appears to have undergone a rapid exponential increase in population size [3, 35]. Among Eurasian vivax malarias, the East Asian variety might have experienced a distinct pattern of population growth [3]. The population of East Asian variety might have been relatively stable in its expansion until approximately 10,000 years BP [36, 37]. It then began to increase rapidly once rice and millet started to be domesticated in the area and sustained such increase, without tapering off, until the present [3]. The inferred hypothesis is suggestive of the detailed evolutionary history of vivax malaria in East Asia [3].

In the phylogenetic tree of P. vivax worldwide, two divergent groups were identified: a large star-like cluster and a divergent cluster [3]. The latter was composed of two subclades with different geographical distributions: “Asia a” of Central China and “Asia b” of China, Korea, and Indonesia. The divergent East Asian P. vivax lineage was connected to the large star-like cluster by a group of haplotypes found in Southeast Asia [3]. Based on the phylogenetic analysis, East Asian P. vivax might have been split from all other vivax malaria and developed a distinct demographic history for at least 121 ka [3]. Meanwhile, mutations of P. vivax-resistant RBCs (Duffy-negative phenotype) occurred in Sub-Saharan peoples [38]. Due to the mutations, vivax malaria disappeared completely from the area until the reintroduction of P. vivax to East Africa by sea-going traders from Asia [39].

3. History of Malaria Infection in Korea

The historical record is important for understanding the pattern of malarial infection in ancient civilizations[27]. In the classical period of Greece, Hippocrates famously described the typical undulating fever, a very suggestive sign of malarial infection [5, 39]. Historians believed that malaria became hyperendemic in Europe by its spread around the Mediterranean area, next along the riverbanks of the Rhine, Danube, and Rhone and then further to Northern Europe, while accommodating to colder climatic conditions in those areas [40]. Historical studies have shown that malaria became remarkably prevalent in the marshy areas of Northern Europe in the Early Middle Ages [5, 40, 41]. By the Later Middle to Early Modern Ages, except for Iceland, plenty of reports on malaria were available from every corner of Europe (including the North Sea, Germany, Anglo-Saxon England, and even Scandinavian countries) [40, 42, 43]. In a sense, malaria appears to have been a much more serious disease than even the Plague [40, 44].

Malaria must have been endemic in East Asia from ancient times as well, as descriptions about malaria-like symptoms can be seen in Chinese historical records [45]. Although Korea had been in close interaction with China from earliest times, in Korean history, the first recorded case of malaria occurred only in the Goryeo Dynasty (918-1392 CE) [46]. In a 14th-century record, a Joseon King’s mother (Joseon Dynasty: 1392-1910 CE) was seriously infected with malaria and eventually died of it [47]. Over the following centuries, a wealth of records on the typical signs and symptoms of malarial infection (intermittent fever, repeated every third day) can be found in the Korean historical literature [47]. As most malarial infection in modern Korea has been revealed to have been caused by P. vivax [48], the Joseon people might have suffered from the same Plasmodium subtype. Notwithstanding the benign traits of P. vivax, relapsed infection typically might have exhausted people, often eventually killing them, as seen in similar clinical reports today [3, 4953].

Before the first modern medical record on malaria in Korea (1886), prevalences of malarial infection could not be reliably calculated. In the First Annual Report of the Korean Government Hospital, Seoul, Dr. Horace Newton Allen described “endemic intermittent fever” (possibly malaria) as the most commonly observed sign among Korean patients who visited his hospital [54, 55]. According to him, in the late 19th century, hyperendemic malaria posed a serious threat to Koreans throughout the entire Joseon Kingdom. How, exactly, did malaria show such a high infection prevalence in Joseon society? In general, wetlands such as scattered swamps, bogs, and river valleys have been important habitats for anopheline mosquito breeding. As wetlands were distributed widely in Korea at that time, they must have been integral to the high malarial transmission rates [34, 40, 5663].

In malariology, however, the waxing and waning of malarial infection in a specific area cannot be explained so simply. In addition to wetlands, environmental alteration or degradation due to human activity also has a great influence on the density and activity of mosquito populations and, further, on the prevalence of malaria itself[6466]. Table 1 summarizes the anthropogenic causes of malaria currently recognized by scholars. As is apparent, people’s efforts to exploit environments often induce outbreaks of malaria [40, 60, 64, 67]. Indeed, agricultural development and malaria are highly correlated in human history [60, 6872]. The expansion of irrigation facilities, the reclamation of wetlands, economic specialization in agriculture, the simplification of crop types, enlargements of rice paddies, high population densities, deforestation, and still other malaria-inducing factors have been commonly cited (Table 1).


Marsh, wetland, coastal area, swamp, etc. as the possible source of malaria infectionIn the African countries, anopheline larvae were abundantly found in the swamps; and topographic wetness (of wetlands) was strongly associated with the spatial distribution of malaria infection cases. The control of wetlands is important for malaria elimination. [34, 40, 5662]
In the late Bronze to early Iron Age Europe, the occupation of the coastal marshes paved the way for the spreading of malaria. Mosquito larvae were able to grow up in stagnant pools and ditches of North Sea or Anglo-Saxon England coast marshes. In European history, the coastal marshes were generally hyperendemic for malaria during 16th to 18th century.

Expansion of irrigation facilitiesIn Ancient Egypt and Rome, Fayum area became the granary by repeated projects of large-scale land reclamation and construction of canal system. Anopheles vector breeding was directly or indirectly linked to the presence of extensive irrigation system. Fayum was seriously exposed to the hazards of malaria by increasing contact between human beings and mosquitos that were bred in the newly developed irrigation system. [2, 60]

Reclamation of wetland for agricultureThe linkage of land reclamation and malaria infection was proven in East Africa. For instance, the elimination of papyrus from the wetlands during land reclamation promotes the breeding of mosquitos and malaria infection. Drainage ditches in newly claimed agricultural land were also the most common breeding site for mosquitos. In brief, the land reclamation was to foster mosquito reproduction by reduced vegetation cover and the elevation of the temperature at breeding site. [2, 60, 124, 125]

Intensified crop cultivation or economic specialization in agricultureEpidemiological study showed that malaria transmission and intensified crops are highly related. The incidence of malaria is about ten times higher in cereals-cultivation area than in areas with less cereals. Intensity of crop cultivation is highly associated with exacerbated human risk of malaria. Specialization in agriculture initially influences on forest loss, and further induces malaria infection (by reducing the biodiversity due to a replacement of huge variety of vegetation with nonnative crops). [2, 64, 124127]

Rice cultivationThe rice paddies provide abundant breeding opportunities for malaria mosquitos. It also becomes a challenging site for vector control. Improper drainage from rice paddies caused Anopheline mosquitos to breed. Mosquito control agents are difficult to be applied to rice paddies. Rice cultivation has a deep-rooted relationship with malaria transmission. [124, 128133]

DeforestationThe pupation rate of Anopheles mosquito was the highest in the samples collected from deforested areas. Land cover pattern is a key factor that influences the habitat for malaria mosquitos. Relationship between deforestation caused by a small-scale farming and Anopheles mosquito breeding was evidently proven in Amazon region. [60, 64, 65, 134144]
In a structural equation model across 67 (developing) nations, positive association was observed between deforestation rates and malaria prevalence. In Sub-Saharan countries, living in the land without trees led to the increased risk of malaria infection. The relationship between land cover and the reproduction of malaria vector mosquitos was also shown in Western Kenyan Highlands.
Epidemiological aspects of ecosystem change (deforestation) and mosquito habitat proliferation (increased levels of larvae, mosquito populations, and actual malaria rates) have been studied extensively. Significant relationship was observed between the percentage of forest cover loss and higher infection prevalence of malaria.
Deforestation impacts malaria prevalence by multiple mechanisms: increase in the sunlight amount, warming temperature ideal for the pupation of malaria vector larvae, standing water after clearing terrain, the land becoming flatter and more likely to store water, which is typically less acidic and more conductive to Anopheles larvae development.
When the forest is replaced by new croplands, the plants still provide the bushy cover for mosquito proliferation, making the malaria infection prevalence higher.

High population densityIn developing countries, rural population growth and needs to increase food production induce the forest loss, further influencing malaria infection. Using the timbers for building and fuel wood is also one of the key causes of deforestation. Growing rural population also tend to live closer to the natural habitats of mosquitos, further experiencing risk of malaria infection. [40, 64, 145147]
In medieval city of Groningen, 10 percent of the urban population died while the surrounding countryside showed a death rate of 5 percent.

We do not yet know whether the close relationship between environmental change by agriculture and malarial infection is a universal phenomenon beyond certain temporal and spatial limits. In a recent cross-national analysis, however, correlations among anthropogenic activity, mosquito population sizes, and malaria rates were seen to have been common in many parts of the world [64]. The findings of Table 1 can thus be applied to our conjecture about Joseon society’s vulnerability to malarial infection. In our careful examination of the Joseon records, we found many similar malarial-infection-facilitating situations to those noted in Table 1. The situations in Joseon society are summarized in Table 2.

Changes in historyDateHistorical detailsReferences

Increase in the ratio of rice paddies to total cultivated land15th to 18th centuryPiling up reservoirs or dams to turn wetlands into rice paddy fields. At the late 17th to 18th century, rice cultivation became dominant in the agriculture of Joseon Dynasty.[63, 73]
18th to 19th centuryChanging cultivated dry fields to the rice paddies (42.9% in 1759 to 68.6% in 1901). One-third of rice paddies of Joseon Kingdom was created at this period.[7375, 78, 79]
Japanese colonial periodChanging the dry field to rice paddies still continued in colonial Korea. Anopheles sinensis, the vector mosquito of malaria in Korea, usually propagates in the stagnant water of rice paddies. Malaria infection was thus very common in the places.[54, 79]
US military administrationTrying to get rid of such mosquito propagation spots by making gutters to drain the water.[79]

Construction of reservoirs or dams15th to 19th centuryFrom the late 15th century on, the irrigation system such as reservoirs and dams were actively built in Korea. The water in the dams could be drained into the paddies for rice cultivation. The construction and maintenance of irrigation system was governed by government or gentries in countryside (16th century). In the early 19th century, the number of reservoirs or dams reached as many as 5,960 in Korea. The construction of dams and reservoirs reached the peak in the early 19th century, maintained even in Japanese colonial period.[54, 63, 74, 75, 78]

Simplification of crop typesSince 18th centuryTo benefits from higher productivity of rice farming and respond the market demands much efficiently, the proportion of rice in cereal cultivation has been greatly expanded.[73]

Clearing and reclamation of the land; Slash and burn in mountain area15th to 18th centuryLarge-scale reclamation was taking place in abandoned land, wetland, coastal, and low-lying areas at river or stream basins (15th to 17th century). Slash and burn increased in mountainous area (since 17th century). Previous ranch and isolated islands were also turned into farmland. The nonfarming backdrops almost disappeared throughout the country after mid-17th century.[7377]

DeforestationSince 17th centuryPopulation growth in Joseon society led to increased demand for forest products. Serious deforestation at this stage was also caused by slash-and-burn farming (after 17th century on). At this stage, approximately 40–50 percent of the cropland in Joseon Kingdom was prepared by slash-and-burn farming, causing deforestation in the mountain area. In mid-17th century, no matter how deep the mountain area was, there was no place where no cropland was. Deforestation induced frequent landslides and floods.[63, 73, 76]
Colonial periodDeforestation appears to have induced malaria in colonial period Korea.[54]

Population increasingMid-16th century9 to 10 million people in Korean peninsula.[73]
Late 18th centuryPopulation in Korean peninsula reached 15 million. The increase in population at this stage appears to have been due to the high productivity of rice cultivation in Korean peninsula at that time.[73, 76]

In brief, the 15th to 19th centuries in Korean history were a turbulent and dynamic period during which the Joseon people were highly motivated to be involved in agricultural innovation, thereby eventually effecting major changes in their sociocultural environment (Table 2). By infusion of labor and capital investments into land development, the state of the agricultural techniques was advanced. By clearing every corner of wasteland and reclaiming wetlands, huge areas of farmland in the Kingdom were newly opened up [7377]. Farmers cleared slash-and-burn fields even up to the tops of mountains[63, 73, 76]. By the end of the Joseon Dynasty, there was virtually no land remaining that had not been utilized for farming purposes (Table 2).

On such lands, Joseon farmers planted crops. Rice was very popular, becoming the most preferred crop by the late Joseon Dynasty [73]. To meet growing market demand for rice, farmers hastily turned their existing dry fields into rice paddies [54, 63, 7375, 78, 79]. To supply enough water for rice cultivation, irrigation systems comprised of reservoirs and dammed pools were newly constructed in the Kingdom [54, 63, 74, 75, 78, 80]. Due to such increased agricultural productivity during the 15th to 19th centuries, the population of the Joseon Kingdom soared [73, 76]. All of these changes meant that the Joseon people came to live more and more in highly populated villages, towns, and cities around which rice paddies, reservoirs, and dams were scattered (Table 2). Certainly, as long as this new situation continued, malarial prevalence was by no means lowered. In a sense, intensive farming appears to have been a necessary evil for the Joseon people, as, notwithstanding the malaria-inductive environments thus created, the increased food production potentiated and achieved thereby was a great economic as well as social boon to the Kingdom.

From the late 19th century, the diagnosis and treatment of malaria began to be performed by specialists in Western medicine. In 1913, for example, an intermittent fever observed among Korean patients was finally confirmed by a modern microbiology technique to be Plasmodium infection [54, 81]. During the Japanese colonial period, however, significant reduction of malarial incidence proved difficult, as the environmental conditions associated with agriculture remained the same. Since the end of World War II and subsequent US army administration, malarial infection as well as its management underwent a revolutionary change in Korea. The US army, which had experienced many deaths from malaria in the course of the war with Japan, was able to establish an effective means of controlling the Plasmodium infection in Asia [79]. Whereas the Japanese during the period of their colonial rule of Korea preferred a strategy entailing curing of malaria patients by quinine treatment at the onset of the disease, the US military administration adopted a far more aggressive and highly effective policy of controlling malaria through the use of insecticides [79].

However, we must also consider the possibility that malarial prevalence in the country was not reduced by antimalarial medications or insecticides alone. This idea is supported by instances in European history. In the 18th to 19th centuries, malaria was still prevalent in Europe, though it rapidly declined thereafter, finally disappearing from most regions by the 1930s [82]. The retreat of malaria from Europe was not the result of medical or chemical innovations, as no such deliberate countermeasures (entailing use of quinine or insecticide, etc.) had been pursued at that time [83]. Rather, another factor has been proposed to explain the decline of malaria in Europe: socioeconomic progress [84]. Many studies in fact have shown a positive correlation between malaria and poverty [85, 86]. Furthermore, it has been established that malaria was active for much longer periods of time in regions where modernization was delayed [40]. In Finland, long-term social changes such as land consolidation, decreasing household size, fewer interactions between families, and the transition from extended family to nuclear family have been posited as causes of malaria’s decline during the past 200 years [83]. In fact, the combined effects of social innovations and improved standards of living were decisive in controlling and eventually eradicating malaria in Europe [40, 60]. Arguably, this explanation is applicable to the decline of malaria in South Korea as well. In that country, malaria was eradicated in the 1970s by the cooperative efforts of the World Health Organization (WHO) and Korea’s National Malaria Eradication Program [48, 87]. Significantly, this corresponded to the period of rapid industrialization by which the living standards of the Korean people were remarkably improved. In short, socioeconomic development in South Korea might have made a great contribution to the eradication of malaria in that country.

Unfortunately, the reemergence of malaria after long-term eradication is not a rare phenomenon in the world[3, 88]. In 1993, after more than two decades of malaria-free status, a new Korean malaria patient was reported among soldiers who had served near the Demilitarized Zone (DMZ) in South Korea [48, 89]. At the time, as North Korea was suffering malarial infection, the new patient was thought to have been infected by an Anopheles mosquito migrating from the north [87, 90]. In fact, this cannot explain everything about the reemergence of malaria in South Korea, as, nowadays at least, foreign travelers and workers from malaria-endemic regions are commonplace [87]. Today, malaria is once again an endemic disease and a source of public concern in South Korea, as cases of malarial infection have continued to be reported [87, 90, 91].

4. Genetic Diversity of Modern Korean P. vivax Isolates

Malarial infection in history often cannot be fully evidenced by the examination of historical documents. This is due to difficulty in accurate diagnosis of ancient malaria cases in history. Actually, the signs and symptoms of ancient malaria patients were often vaguely described in historical literatures by modern clinical medicine standards. In addition, diagnosis of ancient malaria (solely) by the examination of archaeologically obtained skeletal remains is also highly problematic as malaria leaves little traces on bones. In this regard, we note that DNA-based study could be useful for acquiring scientific evidences of specific diseases prevalent in history[27].

DNA analysis of P. vivax is generally targeted on the protozoan parasites’ surface proteins by which the erythrocyte invasion of the vivax-malarial parasite can be triggered [92, 93]. One such surface protein is the P. vivax merozoite surface protein (PvMSP), which is abundantly expressed on the merozoites of vivax malaria [94]. Duffy-binding protein (PvDBP) is another membrane protein that is also present on the P. vivax merozoites and that plays a crucial role in RBC invasion of parasites [92, 93, 95, 96]. As antibodies against these proteins effectively block the invasion of P. vivax into human RBC[91], PvMSP and PvDBP are regarded as leading candidates for use in the development of malaria vaccines[91, 9799] though great genetic diversity among those surface proteins still represent a major obstacle to the vaccine research [4, 91, 97, 100103].

Since the reemergence of P. vivax in South Korea [48, 87], Korean researchers also have aimed to study the genetic traits of vivax malaria’s PvMSP, PvDBP, circumsprozoite protein (PvCSP), apical membrane antigen-1 (AMA-1), microsatellites sequences, and 18S ribosomal RNA genes [87, 90, 91, 103108]. Those scientists are indeed eager to analyze the genetic diversity, population structure, and operation of natural selection among Korean P. vivax isolates, as the outcomes would doubtlessly be useful for understanding the nature of the P. vivax population in South Korea [90, 91, 97]. In general, the genetic diversity of P. vivax is higher than that of P. falciparum, suggesting that the former has a long, complex, but successful evolutionary history of adaptation [4, 109112]. However, when P. vivax reemerged in South Korea, the isolates of the years 1993 to 2000 were genetically closely related, meaning that its genetic diversity was very low at the initial stage of its reintroduction [113]. Since 2001, the reemergent malaria population in South Korea has become more heterogeneous, showing increased genetic diversity and a more complex population structure [87, 89, 97, 108]. The results clearly indicate that some genotypes that were not found before 2000 eventually migrated into South Korea at a much later date, as accompanied by outbreeding between different genotypes [90].

Ju et al. [91] also reported that a phylogenetic analysis based on PvDBPII sequences showed 3 different clusters (SK-1, SK-2, and SK-3) in Korean P. vivax isolates. Among them, SK-3 was a new clade that had not been identified at the early phase of reemergence in the same Korean isolates [106] but later became a more prevalent group than either SK-1 or SK-2 [91]. They agreed that the polymorphic nature of the PvDBPII of recent malarial isolates is distinct from those isolated at the early phase of malaria’s reemergence in South Korea. The value in the rate of nonsynonymous and synonymous mutations (dN-dS) also implied that PvMSP in Korean P. vivax isolates has been under the strong influence of positive natural selection [97] (Figure 1).

5. Paleopathological Approach to Ancient Malaria Infection in Korea

The recent studies on genetic diversity, gene flow, and population structure are also very significant to the development of strategic control measures against vivax malaria after its reemergence in South Korea [90, 112, 116]. Despite all the benefits, however, the overall genetic trends of vivax malaria, especially concerning its evolutionary history, have not yet been revealed by the simple genomic assay of modern isolates. In fact, the investigation of P. vivax using present-day DNA extracts from modern Korean isolates often leads to confusion as to vivax malaria’s origin and dispersal [28]. To overcome this drawback, we must conduct aDNA analyses on various human samples obtained from archaeological sites in Korea to analyze the genetic origin and phylogenetic history of malaria more accurately and comprehensively.

The significance of aDNA analysis to any derived understanding of the evolutionary history of malaria recently has been demonstrated by Gelabert et al. [28]. By way of aDNA analysis on 70-year-old microscopic slides of blood from malaria-infected people in Spain, they were able to successfully reconstruct the mtDNA sequence of the now-eradicated European P. vivax malaria. Moreover, as it was proven to be related to the most common present-day American P. vivax haplotype, the authors were able to confirm that vivax malaria entered the Americas by post-Columbian contact with Europeans [28]. In this way, aDNA assay of ancient human remains can be used for finding the missing links in the origin and spread of ancient malaria.

In aDNA analysis, the types of specimens to choose are very crucial to the research’s success. To select the specimens ideal for aDNA assay purposes, the life-cycle of the vivax-malarial parasite must be considered. In brief, when malarial sporozoites are inoculated into human hosts, some of them migrate to the liver wherein they invade the hepatic parenchymal cells [4]. While some sporozoites can maintain the dormant state there, they can be further differentiated into merozoites and released into the bloodstream [4]. As seen in vivax malaria’s life-cycle, the liver is the place where the final preerythrocytic phase takes place [45]. In this regard, Joseon Dynasty (1392-1910 CE) mummy’s livers might be significant to our project. For the past 10 years, scientists and archaeologists in South Korea have been involved in interdisciplinary work on well-preserved mummies discovered in Joseon Dynasty tombs [117123]. The livers that could be used for aDNA analysis were obtained from mummies by en bloc resection during autopsy (Table 3) [117].

NumberMummyEstimated DateSexDate of excavation

6Hadong2Late 16-early 17Female2009.06
7KunkookJoseon FemaleUnknown

Historical documentation. Carbon dating. Archaeological evidence. Tree ring.

Nevertheless, as the number of malaria sporozoites at liver stage might be actually very small, we should also consider alternate specimens for our aDNA analysis. In this regard, we note that a small amount (less than 1 g) of spongy bones inside vertebrae (possibly containing hemopoietic cell remains) was chosen commonly as specimens for aDNA analysis of malaria; and in another case, first or second molars have been selected for Plasmodium aDNA analysis [27]. Many future studies on ancient malarial genomes will proceed with these specimens of Korean mummies or skeletons.

6. Conclusion

With respect to human samples obtained from archaeological sites, scientific techniques can be done to reveal whether the individual had suffered from malaria in his lifetime or to obtain phylogenetic information of its ancient genome. As the previous studies on ancient malaria have focused mainly on specimens from Egypt and Europe, however, the current information so far obtained carries a serious geographical bias. More extensive geographic samplings and assays are thus needed in order to obtain a more comprehensive demographic evolutionary history of malaria.

Like the other continents, Asia is a region wherein malarial infection has been epidemic in history. Nonetheless, very little has been done in the way of relevant paleopathological studies on ancient malaria. We thus reviewed the history of malaria in Korea and attempted to derive scientific clues to the evolution of P. vivax there and elsewhere in Asia. To those ends, we first examined the historical-documentary evidence of ancient malarial outbreaks in Joseon society and found that malarial epidemics were in fact not unusual in pre-20th-century Korea. We detected changes in the host-vector-pathogen relationship, which probably affected the proliferation of the mosquito vector and indeed the prevalence of ancient malaria in Joseon society. We also noted, in our review of genomic studies on P. vivax, substantial geographic differentiation of vivax-malarial DNA between different continents and even neighboring countries. Many scientific studies on the history of malaria will be done with ancient specimens in Korea and Asia, pending the permission of the relevant medical-ethics review boards.

Conflicts of Interest

The authors declare that there are no conflicts of interest regarding the publication of this paper.

Authors’ Contributions

Dong Hoon Shin and Min Seo contributed equally to this study as first authors.


This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIP) (NRF-2016R1A2B4015669). The authors specially thank Dr. Min Jae Kim (Department of Infectious Diseases, Asan Medical Center, South Korea), for his great advice with regard to our manuscript.


  1. World Health Organization, World malaria report 2011, World Health Organization, Geneva, Switzerland, 2011.
  2. A. Lalremruata, M. Ball, R. Bianucci et al., “Molecular identification of Falciparum malaria and human tuberculosis co-infections in mummies from the Fayum Depression (Lower Egypt),” PLoS ONE, vol. 8, no. 4, Article ID e60307, 2013. View at: Publisher Site | Google Scholar
  3. J. E. Taylor, M. A. Pacheco, D. J. Bacon et al., “The evolutionary history of plasmodium vivax as inferred from mitochondrial genomes: Parasite genetic diversity in the Americas,” Molecular Biology and Evolution, vol. 30, no. 9, pp. 2050–2064, 2013. View at: Publisher Site | Google Scholar
  4. O. E. Cornejo and A. A. Escalante, “The origin and age of Plasmodium vivax,” Trends in Parasitology, vol. 22, no. 12, pp. 558–563, 2006. View at: Publisher Site | Google Scholar
  5. A. Nerlich, “Paleopathology and paleomicrobiology of malaria,” Microbiology Spectrum, vol. 4, no. 6, Article ID PoH-0006-2015, 2016. View at: Publisher Site | Google Scholar
  6. P. Brasil, M. G. Zalis, A. de Pina-Costa et al., “Outbreak of human malaria caused by Plasmodium simium in the Atlantic Forest in Rio de Janeiro: A molecular epidemiological investigation,” The Lancet Global Health, 2017. View at: Publisher Site | Google Scholar
  7. World Health Organization, Guidelines for the Treatment of Malaria, World Health Organization, Geneva, Switzweland, 3rd edition, 2015.
  8. R. Carter and K. N. Mendis, “Evolutionary and historical aspects of the burden of malaria,” Clinical Microbiology Reviews, vol. 15, no. 4, pp. 564–594, 2002. View at: Publisher Site | Google Scholar
  9. M. Miao, Z. Yang, H. Patch, Y. Huang, A. A. Escalante, and L. Cui, “Plasmodium vivax populations revisited: Mitochondrial genomes of temperate strains in Asia suggest ancient population expansion,” BMC Evolutionary Biology, vol. 12, no. 1, article no. 22, 2012. View at: Publisher Site | Google Scholar
  10. L. Huldén, L. Huldén, and K. Heliövaara, “Endemic malaria: An 'indoor' disease in northern Europe. Historical data analysed,” Malaria Journal, vol. 4, no. 19, 2005. View at: Publisher Site | Google Scholar
  11. R. Culleton, C. Coban, F. Y. Zeyrek et al., “The origins of african plasmodium vivax; insights from mitochondrial genome sequencing,” PLoS ONE, vol. 6, no. 12, Article ID e29137, 2011. View at: Publisher Site | Google Scholar
  12. T. J. Setzer, “Malaria detection in the field of paleopathology: A meta-analysis of the state of the art,” Acta Tropica, vol. 140, pp. 97–104, 2014. View at: Publisher Site | Google Scholar
  13. M. N. Cohen, Health and the Rise of Civilization, Yale University Press, New Haven, CT, 1989.
  14. T. D. White and P. A. Folkens, Human Osteology, Academic Press, San Diego, 2000.
  15. T. D. White and P. A. Folkens, The Human Bone Manual, Elsevier Academic, Amsterdam, Boston, 2005.
  16. R. Bianucci, A. Araujo, C. M. Pusch, and A. G. Nerlich, “The identification of malaria in paleopathology-An in-depth assessment of the strategies to detect malaria in ancient remains,” Acta Tropica, vol. 152, pp. 176–180, 2015. View at: Publisher Site | Google Scholar
  17. R. L. Miller, S. Ikram, G. J. Armelagoss et al., “Diagnosis of Plasmodium falciparum infections in mummies using the rapid manual ParaSightTM-F test,” Transactions of the Royal Society of Tropical Medicine and Hygiene, vol. 88, no. 1, pp. 31-32, 1994. View at: Publisher Site | Google Scholar
  18. E. Rabino Massa, N. Cerutti, A. Marin et al., “Malaria in ancient Egypt: paleoimmunological investigations in predynastic mummified remains,” Chungara, vol. 32, no. 1, pp. 7–9, 2000. View at: Google Scholar
  19. R. Bianucci, G. Mattutino, R. Lallo et al., “Immunological evidence of Plasmodium falciparum infection in an Egyptian child mummy from the early dynastic period,” Journal of Archaeological Science, vol. 35, no. 7, pp. 1880–1885, 2008. View at: Publisher Site | Google Scholar
  20. G. Fornaciari, V. Giuffra, E. Ferroglio, and R. Bianucci, “Malaria Was “the Killer” of Francesco I de' Medici (1531-1587),” American Journal of Medicine, vol. 123, no. 6, pp. 568-569, 2010. View at: Publisher Site | Google Scholar
  21. G. Fornaciari, V. Giuffra, E. Ferroglio, S. Gino, and R. Bianucci, “Plasmodium falciparum immunodetection in bone remains of members of the Renaissance Medici family (Florence, Italy, sixteenth century),” Transactions of the Royal Society of Tropical Medicine and Hygiene, vol. 104, no. 9, pp. 583–587, 2010. View at: Publisher Site | Google Scholar
  22. A. G. Nerlich, B. Schraut, S. Dittrich, T. Jelinek, and A. R. Zink, “Plasmodium falciparum in ancient Egypt,” Emerging Infectious Diseases, vol. 14, no. 8, pp. 1317–1319, 2008. View at: Publisher Site | Google Scholar
  23. Z. Hawass, Y. Z. Gad, S. Ismail et al., “Ancestry and pathology in King Tutankhamun's family,” The Journal of the American Medical Association, vol. 303, no. 7, pp. 638–647, 2010. View at: Publisher Site | Google Scholar
  24. R. Khairat, M. Ball, C.-C. H. Chang et al., “First insights into the metagenome of Egyptian mummies using next-generation sequencing,” Journal of Applied Genetics, vol. 54, no. 3, pp. 309–325, 2013. View at: Publisher Site | Google Scholar
  25. R. Sallares and S. Gomzi, “Biomolecular archaeology of malaria,” Ancient Biomolecules, vol. 3, pp. 195–213, 2001. View at: Google Scholar
  26. A. Zink, C. J. Haas, K. Herberth, and A. G. Nerlich, “PCR amplification of Plasmodium DNA in ancient human remains,” Ancient Biomolecules, vol. 3, p. 293, 2001. View at: Google Scholar
  27. S. Marciniak, T. L. Prowse, D. A. Herring et al., “Plasmodium falciparum malaria in 1st–2nd century CE southern Italy,” Current Biology, vol. 26, no. 23, pp. R1220–R1222, 2016. View at: Publisher Site | Google Scholar
  28. P. Gelabert, M. Sandoval-Velasco, I. Olalde et al., “Mitochondrial DNA from the eradicated European Plasmodium vivax and P. falciparum from 70-year-old slides from the Ebro Delta in Spain,” Proceedings of the National Acadamy of Sciences of the United States of America, vol. 113, no. 41, pp. 11495–11500, 2016. View at: Publisher Site | Google Scholar
  29. M. F. Hammer, F. Blackmer, D. Garrigan, M. W. Nachman, and J. A. Wilder, “Human population structure and its effects on sampling Y chromosome sequence variation,” Genetics, vol. 164, no. 4, pp. 1495–1509, 2003. View at: Google Scholar
  30. L. Excoffier, “Patterns of DNA sequence diversity and genetic structure after a range expansion: lessons from the infinite-island model,” Molecular Ecology, vol. 13, no. 4, pp. 853–864, 2004. View at: Publisher Site | Google Scholar
  31. M. Imwong, D. Sudimack, S. Pukrittayakamee et al., “Microsatellite variation, repeat array length, and population history of Plasmodium vivax,” Molecular Biology and Evolution, vol. 23, no. 5, pp. 1016–1018, 2006. View at: Publisher Site | Google Scholar
  32. A. A. Escalante, O. E. Cornejo, D. E. Freeland et al., “A monkey's tale: The origin of Plasmodium vivax as a human malaria parasite,” Proceedings of the National Acadamy of Sciences of the United States of America, vol. 102, no. 6, pp. 1980–1985, 2005. View at: Publisher Site | Google Scholar
  33. J. Mu, D. A. Joy, J. Duan et al., “Host switch leads to emergence of Plasmodium vivax malaria in humans,” Molecular Biology and Evolution, vol. 22, no. 8, pp. 1686–1693, 2005. View at: Publisher Site | Google Scholar
  34. D. E. Loy, W. Liu, Y. Li et al., “Out of Africa: origins and evolution of the human malaria parasites Plasmodium falciparum and Plasmodium vivax,” International Journal for Parasitology, vol. 47, no. 2-3, pp. 87–97, 2017. View at: Publisher Site | Google Scholar
  35. S. Gravel, B. M. Henn, R. N. Gutenkunst et al., “Demographic history and rare allele sharing among human populations,” Proceedings of the National Acadamy of Sciences of the United States of America, vol. 108, no. 29, pp. 11983–11988, 2011. View at: Publisher Site | Google Scholar
  36. H. Lu, J. Zhang, and K.-B. Liu, “Earliest domestication of common millet (Panicum miliaceum) in East Asia extended to 10,000 years ago,” Proceedings of the National Acadamy of Sciences of the United States of America, vol. 106, no. 18, pp. 7367–7372, 2009. View at: Publisher Site | Google Scholar
  37. J. Molina, M. Sikora, N. Garud et al., “Molecular evidence for a single evolutionary origin of domesticated rice,” Proceedings of the National Acadamy of Sciences of the United States of America, vol. 108, no. 20, pp. 8351–8356, 2011. View at: Publisher Site | Google Scholar
  38. L. L. Cavalli-Sforza, P. Menozzi, and A. Piazza, The History and Geography of Human Genes, Princeton University Press, Princeton, New Jersey, USA, 1994.
  39. M. D. Bogdonoff, J. K. Crellin, R. A. Good et al., The Genuine Works of Hippocrates, Classics of Medicine Library, Birmingham, UK, 1985.
  40. O. S. Knottnerus, “Malaria Around the North Sea: A Survey,” in in proceedings of Climatic Development and History of the North Atlantic Realm: Hanse Conference Report, G. Wefer, W. H. Berger, K. E. Behre, and E. Jansen, Eds., pp. 339–353, Springer-Verlag, Berlin Heidelberg, 2002. View at: Google Scholar
  41. O. S. Knottnerus, “Malaria in den Nordseemarschen: Gedanken über Mensch und Umwelt,” in Dünger und Dynamit: Beiträge zur Umweltgeschichte Schleswig-Holsteins und Dänemarks, M. Jakubowski-Tiessen and K. J. Lorenzen-Schmidt, Eds., pp. 25–39, Neumünster, 1999. View at: Google Scholar
  42. E. Meineke and K. Schier, “Fieber,” in Reallexikon der germanischen Altertumskunde, J. Hoops and H. Jankuhn, Eds., vol. 9, pp. 4–11, De Gruyter, Berlin, 2nd edition, 1995. View at: Google Scholar
  43. V. Møller-Christensen, “Feber,” in Kulturhistorisk leksikon for nordisk middelalder fra vikingetid til reformationstid, vol. 4, pp. 208–210, København, Rosenkilde og Bagger, Kopenhagen Oslo Malmö, 1959. View at: Google Scholar
  44. G. Keil, “Malaria,” in Lexikon des Mittelalters, R. Auty et al., Ed., vol. 6, pp. 162-163, Munich, Artemis, 1993. View at: Google Scholar
  45. F. E. Cox, “History of the discovery of the malaria parasites and their vectors,” Parasites & Vectors, vol. 3, no. 1, article 5, 2010. View at: Publisher Site | Google Scholar
  46. H. S. Lee, “Goryeo Period,” in Hangukjeonyeombyueongsa, K. W. Choi et al., Ed., pp. 65–108, The Korean Society of Infectious Diseases, Gunjachulpansa, Seoul, South Korea, 2009. View at: Google Scholar
  47. S. S. Kim, “The first half of Joseon Period,” in Hangukjeonyeombyueongsa, K. W. Choi et al., Ed., pp. 113–200, The Korean Society of Infectious Diseases, Gunjachulpansa, Seoul, South Korea, 2009. View at: Google Scholar
  48. I. H. Chai, G. I. Lim, S. N. Yoon, W. I. Oh, S. J. Kim, and J. Y. Chai, “Occurrence of tertian malaria in a male patient who has never been abroad,” The Korean Journal of Parasitology, vol. 32, no. 3, pp. 195–200, 1994. View at: Publisher Site | Google Scholar
  49. D. K. Kochar, V. Saxena, N. Singh, S. K. Kochar, S. V. Kumar, and A. Das, “Plasmodium vivax malaria,” Emerging Infectious Diseases, vol. 11, no. 1, pp. 132–134, 2005. View at: Publisher Site | Google Scholar
  50. N. M. Anstey, T. Handojo, and M. C. F. Pain, “Lung injury in vivax malaria: pathophysiological evidence for pulmonary vascular sequestration and posttreatment alveolar-capillary inflammation,” The Journal of Infectious Diseases, vol. 195, no. 4, pp. 589–596, 2007. View at: Publisher Site | Google Scholar
  51. M. A. Alexandre, C. O. Ferreira, A. M. Siqueira et al., “Severe Plasmodium vivax malaria, Brazilian Amazon,” Emerging Infectious Diseases, vol. 16, no. 10, pp. 1611–1614, 2010. View at: Publisher Site | Google Scholar
  52. N. M. Douglas, N. M. Anstey, P. A. Buffet et al., “The anaemia of Plasmodium vivax malaria,” Malaria Journal, vol. 11, article 135, 2012. View at: Publisher Site | Google Scholar
  53. V. B. Kute, H. L. Trivedi, A. V. Vanikar et al., “Plasmodium vivax malaria-associated acute kidney injury, India, 2010-2011,” Emerging Infectious Diseases, vol. 18, no. 5, pp. 842–845, 2012. View at: Publisher Site | Google Scholar
  54. I. Yeo, “A history of malaria in modern Korea 1876-1945,” Korean Journal of Medical History, vol. 20, no. 1, pp. 53–82, 2011. View at: Google Scholar
  55. I. Yeo, Allen eui euiryo bogoseo, Yeoksagonggan, Seoul, 2016.
  56. J. M. Chase and T. M. Knight, “Drought-induced mosquito outbreaks in wetlands,” Ecology Letters, vol. 6, no. 11, pp. 1017–1024, 2003. View at: Publisher Site | Google Scholar
  57. J. M. Cohen, K. C. Ernst, K. A. Lindblade, J. M. Vulule, C. C. John, and M. L. Wilson, “Local topographic wetness indices predict household malaria risk better than land-use and land-cover in the western Kenya highlands,” Malaria Journal, vol. 9, no. 1, article no. 328, 2010. View at: Publisher Site | Google Scholar
  58. O. Kenea, M. Balkew, and T. Gebre-Michael, “Environmental factors associated with larval habitats of anopheline mosquitoes (diptera: Culicidae) in irrigation and major drainage areas in the middle course of the rift valley, central ethiopia,” Journal of Vector Borne Diseases, vol. 48, no. 2, pp. 85–92, 2011. View at: Google Scholar
  59. Y. Do, H. A. Kim, S. B. Kim et al., “Awareness and exploitation of wetland during the Joseon Dynasty,” Journal of Wetlands Research, vol. 14, no. 3, pp. 329–340, 2012. View at: Google Scholar
  60. B. Wielgosz, M. Mangheni, D. W. Tsegai, and C. Ringler, “Malaria and Agriculture,” in A global view of the literature with a focus on the application of integrated pest and vector management in East Africa and Uganda, International Food Policy Research Institute, Washington DC, USA, 2012, IFPRI Discussion Paper 01232. View at: Google Scholar
  61. T. Bousema, J. T. Griffin, R. W. Sauerwein et al., “Hitting hotspots: Spatial targeting of malaria for control and elimination,” PLoS Medicine, vol. 9, no. 1, Article ID e1001165, 2012. View at: Publisher Site | Google Scholar
  62. C. J. Shiff, C. Stoyanov, C. Choobwe, A. Kamanga, and V. M. Mukonka, “Measuring malaria by passive case detection: A new perspective based on Zambian experience,” Malaria Journal, vol. 12, no. 1, article no. 120, 2013. View at: Publisher Site | Google Scholar
  63. D. J. Kim, Joseon eui saengtaehwangyeongsa, Purunyeoksa, Seoul, South Korea, 2017.
  64. K. F. Austin, M. O. Bellinger, and P. Rana, “Anthropogenic forest loss and malaria prevalence: a comparative examination of the causes and disease consequences of deforestation in developing nations,” AIMS Environmental Science, vol. 4, no. 2, pp. 217–231, 2017. View at: Publisher Site | Google Scholar
  65. D. E. Norris, “Mosquito-borne Diseases as a Consequence of Land Use Change,” EcoHealth, vol. 1, no. 1, pp. 19–24, 2004. View at: Publisher Site | Google Scholar
  66. S. L. Lewis and M. A. Maslin, “Defining the Anthropocene,” Nature, vol. 519, no. 7542, pp. 171–180, 2015. View at: Publisher Site | Google Scholar
  67. P. Reiter, “Climate change and mosquito-borne disease: Knowing the horse before hitching the cart,” Revue Scientifique et Technique de l'OIE, vol. 27, no. 2, pp. 383–398, 2008. View at: Publisher Site | Google Scholar
  68. W. H. Wernsdorfer and I. McGregor, Malaria: Principles and Practice of Malariology, Churchill Livingstone, Edinburgh, Scotland, 1988.
  69. S. C. Oaks, V. S. Mitchell, G. W. Pearson et al., Malaria: Obstacles and Opportunities, National Academy Press, Washington, DC, USA, 1991.
  70. J. A. Najera, “Malaria Control: Achievements, Problems and Strategies,” Parassitologia, vol. 43, no. 1-2, pp. 1–89, 2001. View at: Google Scholar
  71. J. A. Patz, P. Daszak, G. M. Tabor et al., “Unhealthy landscapes: Policy recommendations on land use change and infectious disease emergence,” Environmental Health Perspectives, vol. 112, no. 10, pp. 1092–1098, 2004. View at: Publisher Site | Google Scholar
  72. R. M. Packard, The Making of a Tropical Disease: A Short History of Malaria, Johns Hopkins University Press, Baltimore, US, 2007.
  73. National Institute of Korean History, Hanguk Munhwasa, National Institute of Korean History, Gwacheon, South Korea, 2009.
  74. J. S. Yeom, “Construction of irrigation facilities in Hwaseong-bu and management of Dunjeon in the late 18th century,” Nongeobsayeongu, vol. 9, no. 1, 2010. View at: Google Scholar
  75. J. S. Yeom, “The agricultural techniques and irrigation facilities in the medieval age-early modern age,” Journal of Central Institute of Cultural Heritage, vol. 10, pp. 99–151, 2012. View at: Google Scholar
  76. C. S. Song, “17, 18 Segi shinjeongaegan eui hwakdae wa gyeongyeongheyongtae,” Hanguksaron, vol. 12, pp. 231–304, 1985, Dept. of Korean History, Seoul National University. View at: Google Scholar
  77. J. S. Yeom, “Reclamation of river islands at lower Daedong river and transition of Gungbangjeon in the Late Joseon Dynasty,” Gyujanggak, vol. 37, pp. 101–130, 2010. View at: Google Scholar
  78. Y. J. Kim, A review for diffusion of rice transplantation and irrigation system during latter period of the Chosun Era [Master, thesis], Inha University, Incheon, South Korea, 2001.
  79. I.-S. Yeo, “U.S. military administration's malaria control activities (1945-1948),” Korean Journal of Medical History, vol. 24, no. 1, pp. 35–65, 2015. View at: Publisher Site | Google Scholar
  80. C.-Y. Jung, “Regional characteristics of Cheon during the Late Choson Era as seen through the Yojitoso,” Journal of the Korean Geographical Society, vol. 43, no. 4, pp. 620–637, 2008 (Korean). View at: Google Scholar
  81. C. Y. Chow, “Arthropods of public health importance in Korea,” Korean Journal of Entomology, vol. 3, no. 1, pp. 43-44, 1973. View at: Google Scholar
  82. L. Huldén, L. Huldén, and K. Heliövaara, “Endemic malaria: An 'indoor' disease in northern Europe. Historical data analysed,” Malaria Journal, vol. 25, no. 4, 2005. View at: Google Scholar
  83. L. Hulden and L. Hulden, “The decline of malaria in Finland - The impact of the vector and social variables,” Malaria Journal, vol. 8, no. 1, article no. 94, 2009. View at: Publisher Site | Google Scholar
  84. J. de Zulueta, “Malaria and ecosystems: from prehistory to posteradication.,” Parassitologia, vol. 36, no. 1-2, pp. 7–15, 1994. View at: Google Scholar
  85. J. L. Gallup and J. D. Sachs, “The economic burden of malaria,” The American Journal of Tropical Medicine and Hygiene, vol. 64, no. 1-2, pp. 85–96, 2001. View at: Publisher Site | Google Scholar
  86. R. I. Chima, C. A. Goodman, and A. Mills, “The economic impact of malaria in Africa: A critical review of the evidence,” Health Policy, vol. 63, no. 1, pp. 17–36, 2003. View at: Publisher Site | Google Scholar
  87. Y.-K. Choi, K.-M. Choi, M.-H. Park et al., “Rapid dissemination of newly introduced Plasmodium vivax genotypes in South Korea,” The American Journal of Tropical Medicine and Hygiene, vol. 82, no. 3, pp. 426–432, 2010. View at: Publisher Site | Google Scholar
  88. C. A. Guerra, S. I. Hay, L. S. Lucioparedes et al., “Assembling a global database of malaria parasite prevalence for the Malaria Atlas Project,” Malaria Journal, vol. 6, article no. 17, 2007. View at: Publisher Site | Google Scholar
  89. J. W. Park, T. A. Klein, H. C. Lee et al., “Vivax malaria: A continuing health threat to the Republic of Korea,” The American Journal of Tropical Medicine and Hygiene, vol. 69, pp. 159–167, 2003. View at: Google Scholar
  90. H. Honma, J.-Y. Kim, N. M. Q. Palacpac et al., “Recent increase of genetic diversity in Plasmodium vivax population in the Republic of Korea,” Malaria Journal, vol. 10, article no. 257, 2011. View at: Publisher Site | Google Scholar
  91. H.-L. Ju, J.-M. Kang, S.-U. Moon et al., “Genetic diversity and natural selection of Duffy binding protein of Plasmodium vivax Korean isolates,” Acta Tropica, vol. 125, no. 1, pp. 67–74, 2013. View at: Publisher Site | Google Scholar
  92. J. W. Barnwell, M. E. Nichols, and P. Rubinstein, “In vitro evaluation of the role of the Duffy blood group in erythrocyte invasion by Plasmodium vivax,” The Journal of Experimental Medicine, vol. 169, no. 5, pp. 1795–1802, 1989. View at: Publisher Site | Google Scholar
  93. J. H. Adams, B. K. L. Sim, S. A. Dolan, X. Fang, D. C. Kaslow, and L. H. Miller, “A family of erythrocyte binding proteins of malaria parasites,” Proceedings of the National Acadamy of Sciences of the United States of America, vol. 89, no. 15, pp. 7085–7089, 1992. View at: Publisher Site | Google Scholar
  94. A. A. Holder, J. A. Guevara Patino, and C. Uthaipibull, “Merozoite surface protein 1, immune evasion, and vaccines against asexual blood stage malaria,” Parasitologia, vol. 41, pp. 409–414, 1999. View at: Google Scholar
  95. S. P. Wertheimer and J. W. Barnwell, “Plasmodium vivax interaction with the human Duffy blood group glycoprotein: Identification of a parasite receptor-like protein,” Experimental Parasitology emphasizes, vol. 69, no. 3, pp. 340–350, 1989. View at: Publisher Site | Google Scholar
  96. R. Horuk, C. E. Chitnis, W. C. Darbonne et al., “A receptor for the malarial parasite Plasmodium vivax: The erythrocyte chemokine receptor,” Science, vol. 261, no. 5125, pp. 1182–1184, 1993. View at: Publisher Site | Google Scholar
  97. J.-M. Kang, H.-L. Ju, Y.-M. Kang et al., “Genetic polymorphism and natural selection in the C-terminal 42kDa region of merozoite surface protein-1 among Plasmodium vivax Korean isolates,” Malaria Journal, vol. 11, article no. 206, 2012. View at: Publisher Site | Google Scholar
  98. M. Arévalo-Herrera and S. Herrera, “Plasmodium vivax malaria vaccine development,” Molecular Immunology, vol. 38, no. 6, pp. 443–455, 2001. View at: Publisher Site | Google Scholar
  99. A. A. Holder, “Malaria vaccines: Where next?” PLoS Pathogens, vol. 5, no. 10, Article ID e1000638, 2009. View at: Publisher Site | Google Scholar
  100. M. C. Bruce, M. R. Galinski, J. W. Barnwell, G. Snounou, and K. P. Day, “Polymorphism at the merozoite surface protein-3α locus of Plasmodium vivax: global and local diversity,” The American Journal of Tropical Medicine and Hygiene, vol. 61, no. 4, pp. 518–525, 1999. View at: Publisher Site | Google Scholar
  101. J. C. Rayner, V. Corredor, D. Feldman et al., “Extensive polymorphism in the Plasmodium vivax merozoite surface coat protein MSP-3α is limited to specific domains,” Parasitology, vol. 125, no. 5, pp. 393–405, 2002. View at: Publisher Site | Google Scholar
  102. M. C. Leclerc, C. Gauthier, L. Villegas, and L. Urdaneta, “Genetic diversity of merozoite surface protein-1 gene of Plasmodium vivax isolates in mining villages of Venezuela (Bolivar State),” Acta Tropica, vol. 95, no. 1, pp. 26–32, 2005. View at: Publisher Site | Google Scholar
  103. J.-Y. Chai, Y.-K. Park, S.-M. Guk et al., “A trial for a DNA diagnosis of Plasmodium vivax malaria recently reemerging in the republic of korea using microtiter plate hybridization assay,” The American Journal of Tropical Medicine and Hygiene, vol. 63, no. 1-2, pp. 80–84, 2000. View at: Publisher Site | Google Scholar
  104. C. S. Lim, S. H. Kim, S. I. Kwon, J.-W. Song, K.-J. Song, and K. N. Lee, “Analysis of Plasmodium vivax merozoite surface protein-1 gene sequences from resurgent Korean isolates,” The American Journal of Tropical Medicine and Hygiene, vol. 62, no. 2, pp. 261–265, 2000. View at: Publisher Site | Google Scholar
  105. C. S. Lim, Y. K. Kim, K. N. Lee et al., “The analysis of circumsporozoite-protein gene sequences from South Korean isolates of,” Annals of Tropical Medicine & Parasitology, vol. 95, no. 3, pp. 229–235, 2016. View at: Publisher Site | Google Scholar
  106. W. G. Kho, J. Y. Chung, E. J. Sim, D. W. Kim, and W. C. Chung, “Analysis of polymorphic regions of Plasmodium vivax Duffy binding protein of Korean isolates.,” The Korean Journal of Parasitology, vol. 39, no. 2, pp. 143–150, 2001. View at: Publisher Site | Google Scholar
  107. J.-Y. Chung, E.-H. Chun, J.-H. Chun, and W.-G. Kho, “Analysis of the Plasmodium vivax apical membrane antigen-1 gene from re-emerging Korean isolates,” Parasitology Research, vol. 90, no. 4, pp. 325–329, 2003. View at: Publisher Site | Google Scholar
  108. D. H. Nam, J. S. Oh, M. H. Nam et al., “Emergence of new alleles of the MSP-3alpha gene in Plasmodium vivax isolates from Korea,” The American Journal of Tropical Medicine and Hygiene, vol. 82, no. 4, pp. 522–524, 2010. View at: Publisher Site | Google Scholar
  109. D. E. Neafsey, K. Galinsky, R. H. Y. Jiang et al., “The malaria parasite Plasmodium vivax exhibits greater genetic diversity than Plasmodium falciparum,” Nature Genetics, vol. 44, no. 9, pp. 1046–1050, 2012. View at: Publisher Site | Google Scholar
  110. P. Orjuela-Sánchez, J. M. Sá, M. C. C. Brandi et al., “Higher microsatellite diversity in Plasmodium vivax than in sympatric Plasmodium falciparum populations in Pursat, Western Cambodia,” Experimental Parasitology emphasizes, vol. 134, no. 3, pp. 318–326, 2013. View at: Publisher Site | Google Scholar
  111. W. Liu, Y. Li, K. S. Shaw et al., “African origin of the malaria parasite Plasmodium vivax,” Nature Communications, vol. 5, p. 3346, 2014. View at: Google Scholar
  112. A. E. Barry, A. Waltmann, C. Koepfli, C. Barnadas, and I. Mueller, “Uncovering the transmission dynamics of Plasmodium vivax using population genetics,” Pathogens and Global Health, vol. 109, no. 3, pp. 142–152, 2015. View at: Publisher Site | Google Scholar
  113. M. Iwagami, S.-Y. Hwang, S.-H. Kim et al., “Microsatellite DNA Analysis Revealed a Drastic Genetic Change of Plasmodium vivax Population in the Republic of Korea During 2002 and 2003,” PLOS Neglected Tropical Diseases, vol. 7, no. 10, Article ID e2522, 2013. View at: Publisher Site | Google Scholar
  114. K. Tamura, G. Stecher, D. Peterson, A. Filipski, and S. Kumar, “MEGA6: Molecular Evolutionary Genetics Analysis version 6.0,” Molecular Biology and Evolution, vol. 30, no. 12, pp. 2725–2729, 2013. View at: Publisher Site | Google Scholar
  115. B. G. Hall, “Building phylogenetic trees from molecular data with MEGA,” Molecular Biology and Evolution, vol. 30, no. 5, pp. 1229–1235, 2013. View at: Publisher Site | Google Scholar
  116. L. Cui, A. A. Escalante, M. Imwong, and G. Snounou, “The genetic diversity of Plasmodium vivax populations,” Trends in Parasitology, vol. 19, no. 5, pp. 220–226, 2003. View at: Publisher Site | Google Scholar
  117. Y. S. Kim, M. J. Kim, and J. H. Hong, “The Scientific and Ethical Background of the Invasive Studies on the Korean Mummies of the Joseon Dynasty,” Asian Journal of Paleopathology, vol. 1, pp. 5–11, 2017. View at: Google Scholar
  118. I. S. Lee, E.-J. Lee, J. B. Park et al., “Acute traumatic death of a 17th century general based on examination of mummified remains found in Korea,” Annals of Anatomy, vol. 191, no. 3, pp. 309–320, 2009. View at: Publisher Site | Google Scholar
  119. D. H. Shin, C. S. Oh, S. J. Lee et al., “Ectopic paragonimiasis from 400-year-old female mummy of Korea,” Journal of Archaeological Science, vol. 39, no. 4, pp. 1103–1110, 2012. View at: Publisher Site | Google Scholar
  120. D. H. Shin, C. S. Oh, H. J. Lee et al., “Ancient DNA analysis on Clonorchis sinensis eggs remained in samples from medieval Korean mummy,” Journal of Archaeological Science, vol. 40, no. 1, pp. 211–216, 2013. View at: Publisher Site | Google Scholar
  121. E.-J. Lee, C. S. Oh, S. G. Yim et al., “Collaboration of Archaeologists, Historians and Bioarchaeologists During Removal of Clothing from Korean Mummy of Joseon Dynasty,” International Journal of Historical Archaeology, vol. 17, no. 1, pp. 94–118, 2013. View at: Publisher Site | Google Scholar
  122. M. Seo, A. Araujo, K. Reinhard, J. Y. Chai, and D. H. Shin, “Paleoparasitological studies on mummies of the Joseon Dynasty, Korea,” The Korean Journal of Parasitology, vol. 52, no. 3, pp. 235–242, 2014. View at: Publisher Site | Google Scholar
  123. Y.-S. Kim, I. S. Lee, C. S. Oh, M. J. Kim, S. C. Cha, and D. H. Shin, “Calcified pulmonary nodules identified in a 350-year-old-joseon mummy: The first report on ancient pulmonary tuberculosis from archaeologically obtained pre-modern Korean samples,” Journal of Korean Medical Science, vol. 31, no. 1, pp. 147–151, 2016. View at: Publisher Site | Google Scholar
  124. J. Keiser, M. C. De Castro, M. F. Maltese et al., “Effect of irrigation and large dams on the burden of malaria on a global and regional scale,” The American Journal of Tropical Medicine and Hygiene, vol. 72, no. 4, pp. 392–406, 2005. View at: Google Scholar
  125. K. Asenso-Okyere, F. A. Asante, J. Tarekegn et al., “The Linkages between Agriculture and Malaria. Issues for Policy, Research and Capacity Strengthening,” in Proceedings of the IFPRI Discussion Paper 00861, International Food Policy Research Institute, Washington DC, USA, 2009. View at: Google Scholar
  126. S. S. Myers, L. Gaffikin, C. D. Golden et al., “Human health impacts of ecosystem alteration,” Proceedings of the National Acadamy of Sciences of the United States of America, vol. 110, no. 47, pp. 18753–18760, 2013. View at: Publisher Site | Google Scholar
  127. G. Z. Laporta, P. I. K. L. D. Prado, R. A. Kraenkel, R. M. Coutinho, and M. A. M. Sallum, “Biodiversity Can Help Prevent Malaria Outbreaks in Tropical Forests,” PLOS Neglected Tropical Diseases, vol. 7, no. 3, Article ID e2139, 2013. View at: Publisher Site | Google Scholar
  128. J. A. Carney, Black Rice: The African Origins of Rice Cultivation in the Americas, Harvard University Press, Cambridge, MA, USA, 2001.
  129. J. N. Ijumba and S. W. Lindsay, “Impact of irrigation on malaria in Africa: Paddies paradox,” Medical and Veterinary Entomology, vol. 15, no. 1, pp. 1–11, 2001. View at: Publisher Site | Google Scholar
  130. E. Klinkenberg, W. Takken, F. Huibers, and Y. T. Touré, “The phenology of malaria mosquitoes in irrigated rice fields in Mali,” Acta Tropica, vol. 85, no. 1, pp. 71–82, 2003. View at: Publisher Site | Google Scholar
  131. G. Dolo, O. J. T. Briët, A. Dao et al., “Malaria transmission in relation to rice cultivation in the irrigated Sahel of Mali,” Acta Tropica, vol. 89, no. 2, pp. 147–159, 2004. View at: Publisher Site | Google Scholar
  132. P. N. Ng'ang'a, J. Shililu, G. Jayasinghe et al., “Malaria vector control practices in an irrigated rice agro-ecosystem in central Kenya and implications for malaria control,” Malaria Journal, vol. 7, article no. 146, 2008. View at: Publisher Site | Google Scholar
  133. J. M. Mwangangi, J. Shililu, E. J. Muturi et al., “Anopheles larval abundance and diversity in three rice agro-village complexes Mwea irrigation scheme, central Kenya,” Malaria Journal, vol. 9, no. 1, article no. 228, 2010. View at: Publisher Site | Google Scholar
  134. J. A. Patz, T. K. Graczyk, N. Geller, and A. Y. Vittor, “Effects of environmental change on emerging parasitic diseases,” International Journal for Parasitology, vol. 30, no. 12-13, pp. 1395–1405, 2000. View at: Publisher Site | Google Scholar
  135. S. Munga, N. Minakawa, G. Zhou et al., “Association between land cover and habitat productivity of malaria vectors in western Kenyan highlands,” The American Journal of Tropical Medicine and Hygiene, vol. 74, no. 1, pp. 69–75, 2006. View at: Google Scholar
  136. A. Y. Vittor, R. H. Gilman, J. Tielsch et al., “The effect of deforestation on the human-biting rate of Anopheles darlingi, the primary vector of Falciparum malaria in the Peruvian Amazon,” The American Journal of Tropical Medicine and Hygiene, vol. 74, no. 1, pp. 3–11, 2006. View at: Google Scholar
  137. J. Yasuoka and R. Levins, “Impact of deforestation and agricultural development on anopheline ecology and malaria epidemiology,” The American Journal of Tropical Medicine and Hygiene, vol. 76, no. 3, pp. 450–460, 2007. View at: Google Scholar
  138. K. C. Ernst, K. A. Lindblade, D. Koech et al., “Environmental, socio-demographic and behavioural determinants of malaria risk in the western Kenyan highlands: A case-control study,” Tropical Medicine & International Health, vol. 14, no. 10, pp. 1258–1265, 2009. View at: Publisher Site | Google Scholar
  139. A. Y. Vittor, W. Pan, R. H. Gilman et al., “Linking deforestation to malaria in the Amazon: characterization of the breeding habitat of the principal malaria vector, Anopheles darlingi,” The American Journal of Tropical Medicine and Hygiene, vol. 81, no. 1, pp. 5–12, 2009. View at: Publisher Site | Google Scholar
  140. E. Teferi, S. Uhlenbrook, W. Bewket, J. Wenninger, and B. Simane, “The use of remote sensing to quantify wetland loss in the Choke Mountain range, Upper Blue Nile basin, Ethiopia,” Hydrology and Earth System Sciences, vol. 14, no. 12, pp. 2415–2428, 2010. View at: Publisher Site | Google Scholar
  141. B. H. Manh, A. C. A. Clements, N. Q. Thieu et al., “Social and environmental determinants of malaria in space and time in Viet Nam,” International Journal for Parasitology, vol. 41, no. 1, pp. 109–116, 2011. View at: Publisher Site | Google Scholar
  142. A. Midekisa, G. B. Senay, and M. C. Wimberly, “Multisensor earth observations to characterize wetlands and malaria epidemiology in Ethiopia,” Water Resources Research, vol. 50, no. 11, pp. 8791–8806, 2014. View at: Publisher Site | Google Scholar
  143. W. Hanandita and G. Tampubolon, “Geography and social distribution of malaria in Indonesian Papua: A cross-sectional study,” International Journal of Health Geographics, vol. 15, no. 1, article no. 13, 2016. View at: Publisher Site | Google Scholar
  144. X. Wang, G. Zhou, D. Zhong et al., “Life-table studies revealed significant effects of deforestation on the development and survivorship of Anopheles minimus larvae,” Parasites & Vectors, vol. 9, no. 1, article no. 323, 2016. View at: Publisher Site | Google Scholar
  145. A. K. Jorgenson and T. J. Burns, “Effects of rural and urban population dynamics and national development on deforestation in less-developed countries, 1990-2000,” Sociological Inquiry, vol. 77, no. 3, pp. 460–482, 2007. View at: Publisher Site | Google Scholar
  146. T. Bensel, “Fuelwood, deforestation, and land degradation: 10 years of evidence from Cebu province, the Philippines,” Land Degradation & Development, vol. 19, no. 6, pp. 587–605, 2008. View at: Publisher Site | Google Scholar
  147. K. F. Austin, M. D. Noble, and M. T. Mejia, “Gendered vulnerabilities to a neglected disease: A comparative investigation of the effect of women’s legal economic rights and social status on malaria rates,” International Journal of Comparative Sociology, vol. 55, no. 3, pp. 204–228, 2014. View at: Publisher Site | Google Scholar

Copyright © 2018 Dong Hoon Shin et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

More related articles

 PDF Download Citation Citation
 Download other formatsMore
 Order printed copiesOrder

Related articles

Article of the Year Award: Outstanding research contributions of 2020, as selected by our Chief Editors. Read the winning articles.