Sato Journal of Physiological Anthropology
https://doi.org/10.1186/s40101-020-00251-9(2021) 40:1

REVIEW

Open Access

Plasmodium—a brief introduction to theparasites causing human malaria and theirbasic biology
Shigeharu Sato1,2

Abstract
Malaria is one of the most devastating infectious diseases of humans. It is problematic clinically and economicallyas it prevails in poorer countries and regions, strongly hindering socioeconomic development. The causative agentsof malaria are unicellular protozoan parasites belonging to the genus Plasmodium. These parasites infect not only
humans but also other vertebrates, from reptiles and birds to mammals. To date, over 200 species of Plasmodium
have been formally described, and each species infects a certain range of hosts. Plasmodium species that naturally
infect humans and cause malaria in large areas of the world are limited to five—P. falciparum, P. vivax, P. malariae,
P. ovale and P. knowlesi. The first four are specific for humans, while P. knowlesi is naturally maintained in macaquemonkeys and causes zoonotic malaria widely in South East Asia. Transmission of Plasmodium species between
vertebrate hosts depends on an insect vector, which is usually the mosquito. The vector is not just a carrier but thedefinitive host, where sexual reproduction of Plasmodium species occurs, and the parasite’s development in theinsect is essential for transmission to the next vertebrate host. The range of insect species that can support thecritical development of Plasmodium depends on the individual parasite species, but all five Plasmodium species
causing malaria in humans are transmitted exclusively by anopheline mosquitoes. Plasmodium species haveremarkable genetic flexibility which lets them adapt to alterations in the environment, giving them the potential toquickly develop resistance to therapeutics such as antimalarials and to change host specificity. In this article,
selected topics involving the Plasmodium species that cause malaria in humans are reviewed.
Keywords: Antimalarial, Asymptomatic carrier, Drug resistance, Host specificity, Host switch, Malaria, Mosquito,
Plasmodium, Recurrence, Zoonosis

Background: battle of humans against
malaria—past and present
Malaria has been recognised as a serious health problem
since the earliest historical times. This disease is caused
by protozoan parasites belonging to the genus Plasmodium. The strong negative pressure of the disease has
Correspondence: ukssato@gmail.com
1
Borneo Medical and Health Research Centre, Faculty of Medicine and Health
Sciences, Universiti Malaysia Sabah, Jalan UMS, 88400 Kota Kinabalu, Sabah,
Malaysia2
Department of Pathobiology and Medical Diagnostics, Faculty of Medicine
and Health Sciences, Universiti Malaysia Sabah, Jalan UMS, 88400 Kota
Kinabalu, Sabah, Malaysia

likely forced the evolution of human populations in malaria endemic regions and the selection of some uniquegenetic variants. For example, thalassemia and sickle-cell
disease, each of which is a genetic disorder affecting red
blood cells, are commonly found in malaria endemicareas [1], and people with these two disorders show resistance to malaria. Another well-known example is the
Duffy-negative blood type that the majority of people living in Central and West Africa have [2]. This confers
specific resistance to infection by one particular Plasmodium species, P. vivax [3, 4]. The spread of this trait in
the population is estimated to have begun around 42,© The Author(s). 2021, corrected publication 2021. Open Access This article is licensed under a Creative Commons Attribution
4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, aslong as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence,and indicate if changes were made. The images or other third party material in this article are included in the article's Creative
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Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need
to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/
licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.
0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Sato Journal of Physiological Anthropology(2021) 40:1

000 years ago [5], and today P. vivax malaria is rare inthese areas whereas P. falciparum malaria is prevalent[6].
Even in the modern world with effective antimalarials
and insecticide-treated bed nets (ITNs), people in many
countries remain at risk, and the number of malaria
cases, particularly those resulting from P. falciparumthat causes the most serious infection, remains high ineconomically poor countries, especially in Africa [7].
Rolling out adequate and continuous programmes to effectively control malaria has been difficult mainly due tolack of finance. In 2000, the health programme to “combat malaria” was selected as one of the critical global targets of the Millennium Development Goals set by theUnited Nations. This global effort was to achieve the targets that were set for measurable health indicators, suchas disease prevalence, death rates and protection of children under 5-years of age with ITNs and appropriate
antimalarial drugs. In 2005, the sum of global investments for malaria control was an estimated US$960 million, mostly from National Malaria Control Programmes(NMCPs) [7]. Whilst contributions from NMCPs
remained at the same level, investments from othersources started to increase steadily since 2006. As a result, the sum of global investments surpassed US$2000
million in 2009 and has remained almost at this level
thereafter [7]. With this extra financing, malaria control
programs achieved a remarkable level of progress globally. For example, in 2000, the annual deaths caused bymalaria in the entire world and in Africa were estimatedto be 839,000 (between 653,000 and 1.1 million) and
694,000 (569,000–901,000), respectively. By 2015, thesenumbers had been reduced to 483,000 (236,000–635,000) and 292,000 (212,000–384,000) [7]. The number ofcountries estimated to have fewer than 1000 indigenous
malaria cases increased from 13 in 2000 to 33 in 2015[7], and six countries (United Arab Emirates, Morocco,
Armenia, Turkmenistan, Kyrgyzstan and Sri Lanka)
achieved at least 3 consecutive years of zero indigenous
cases between 2000 and 2015 and were certified as malaria free by WHO [8].
Plasmodium species infecting humans share a similarlife cycle with an initial development phase in the liverand subsequent further proliferation in the blood of thehost. They also show a similar susceptibility to some
antimalarial drugs such as quinine, chloroquine and artemisinin, as well as the development of resistance tothese drugs [9, 10]. Transmission is also mediated by thesame group of anopheline mosquitoes [11]. P. vivax malaria can relapse after chemotherapy with drugs that kill
the parasites only in the intraerythrocytic development
stage [12], but 8-aminoquinolines such as primaquine
are known to prevent this effectively [13]. Thus, systematic control programmes involving appropriate

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chemotherapy including administration of primaquine topatients with P. vivax malaria, as well as proper mosquito control, can simultaneously reduce the number ofmalaria incidents caused by any Plasmodium species.
There have been reports of malaria in humans causedby other Plasmodium species that naturally infect otherprimate hosts. But zoonotic malaria is rare, except forthat caused by P. knowlesi, which naturally infects macaque monkeys such as the long-tailed and the pig-tailed
macaques (Macaca fascicularis and M. nemestrina, respectively). Human infection by P. knowlesi has been reported since the 1960s [14, 15], but it had been longthought exceptional like other zoonotic malarias.
The NMCP rolled out in Malaysia in the 1960s had
achieved a dramatic reduction of the number of humanmalaria cases caused by P. falciparum and P. vivax inSarawak in Malaysian Borneo by the late 1990s–early
2000s. By contrast, the incidence of P. malariae which israther rare in that state [16] showed an apparent increase [17]. At that time, the species of Plasmodium
present in patients in Sarawak was identified solely by
microscopical observation of parasites in blood films.
However, a molecular diagnosis combining nested PCR
and DNA sequencing revealed that most of the malaria
cases attributed to P. malariae by microscopy were actually caused by P. knowlesi [18]. Following the identification of human cases of P. knowlesi in Sarawak, similarcases were identified in neighbouring Sabah state [19]and within the Peninsular Malaysia [20]. Human infections of P. knowlesi have also been reported in other
South East Asian countries including Vietnam andThailand [17], and P. knowlesi malaria is now recognised
as the fifth human malaria [21]. It has been confirmedthat P. knowlesi can produce gametocytes in patients
who naturally acquire the infection [22], although transmission of P. knowlesi malaria between humans has notbeen reported yet. The clinical importance of P. knowlesi
malaria is particularly high in Malaysia, where malaria
caused by the other four human-infective species has
been almost completely eliminated thanks to the successful NMCP [6]. Now, almost all malaria cases identified in the country are caused by P. knowlesi.
Like P. knowlesi, other Plasmodium species that naturally infect non-human primates have been considered as
potential threats to human health through zoonosis [23,24]. Macaques in Sarawak in Malaysian Borneo are
known to be the reservoir of six Plasmodium species—P.
knowlesi, P. inui, P. cynomolgi, P. coatneyi, P. fieldi andP. simiovale [25]. Of these, P. cynomolgi has been provento naturally cause human infection [26], and P. inui canestablish an infection when experimentally introduced
into humans [27]. Clinical cases of zoonotic malaria
caused by these species are currently either extremelyrare (P. cynomolgi) or unreported (P. inui), but they

Sato Journal of Physiological Anthropology(2021) 40:1

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might become the next Plasmodium species to significantly affect human health in the future.
Zoonotic malaria has been reported in South America
as well. The species of Plasmodium implicated there are
P. simium [28] and P. brasilianum [29], parasites thatnaturally infect platyrrhine monkeys. The two species, P.
simium and P. brasilianum, have been shown to bephylogenetically very close to P. vivax and P. malariae,
respectively [30].

Malaria and Plasmodium biology
Life cycle of Plasmodium

All Plasmodium species share a similar life cycle [31]. It
has two parts—in the first, the parasite infects a person(or a vertebrate host), and in the second, it is transmitted from the malaria patient (or infected vertebrate host)to another host by an insect vector. The vectors thattransmit the five Plasmodium species naturally infecting
humans are mosquitoes of the genus Anopheles. These
mosquitoes also transmit other Plasmodium species
parasitising other mammals whereas transmission of
Plasmodium infecting birds and reptiles depends on
mosquitoes of other genera or other blood-sucking insects [32].
The Plasmodium life cycle begins when parasites
known as sporozoites produced in the insect vector
enter the blood of the vertebrate host following a bite[33]. Sporozoites deposited in the dermis [34] rapidly
migrate to the liver and invade hepatocytes where they
multiply by thousands—a process known as schizogony[35]. The resulting parasites, now called merozoites, arereleased back into the blood [36] and infect erythrocytes.
In an erythrocyte, one merozoite multiplies asexually by
schizogony to generate between 8 and 64 new merozoites (the number depending on the species) [37]. These
new merozoites are released back to the blood, and theparasites repeat this intraerythrocytic propagation cycle
every 24 (P. knowlesi), 48 (P. falciparum, P. ovale, P.
vivax) or 72 (P. malariae) hours. Some merozoites thendifferentiate into the next developmental stage called thegametocyte for sexual reproduction [38, 39]. Just whengametocyte differentiation (gametocytogenesis) starts depends on the species. For example, P. falciparum needs
to complete several cycles of intraerythrocytic propagation before it starts differentiation into gametocytes,
whereas P. vivax continuously produces gametocyteseven in its early intraerythrocytic propagation cycles(Table 1). While each gametocyte has a similar appearance during its early development, they are already programmed to differentiate into either male or female
gametes (gametogenesis, sexually committed). This completes the part of the parasites’ life cycle that occurs inside the human body. Development beyond thegametocyte stage normally takes place following a blood
meal, in the lumen of the mosquito midgut, where themale and the female gametes fuse [52]. However, there
are sporadic reports of exflagellated forms (male gametes) of P. falciparum observed in the human body [53].
The second part of the life cycle in the insect vector
begins when the insect ingests the blood containing gametocytes from an infected vertebrate host. The gametocytes are activated once exposed to the specific

Table 1 Onset of gametocyte production and recurrence in human malaria
Causative
species

Onset of gametocyte production

RelapseRecrudescenceP.
falciparum

After several rounds of intraerythrocytic asexual
reproduction (“gametocytes may make theirappearance in small numbers on or about the 10th
day following the first day of fever, and their
numbers increase rapidly day by day for 2 or 3
weeks” [40])Unknown (hypnozoites not observed yet)

Known to occur (latent
period usually < 2 months,
but can be > 2 years [41])P. vivax

Continuous from early rounds of intraerythrocytic
asexual reproduction (“sexual forms may occur as
early as the 6th or 7th day, reaching their maximum
number on or about the 10th day” [40])Well documented (latency period ranges from < 2weeks to > 1 year and varies systematically bygeographic region [42]; hypnozoites in liverobserved [43]; estimated to be majority ofrecurrence [44])Unknown

Unknown (hypnozoites not observed yet)

Known to occur (latent
period can be > 40 years[47])

P. malariae Probably continuous from early rounds ofintraerythrocytic asexual reproduction (after a
prepatent period (16–59 days [45]), gametocytes
emerges in patient’s blood together withintraerythrocytic parasites [46])Recurrence

P. ovaleContinuous from early rounds of intraerythrocytic
asexual reproduction (“[gametocytes] appear in the
peripheral blood a little earlier than in B.T. [benign
tertian]” [40])Clinical cases reported [48]; molecular evidence fora causal relationship between dormant liver stages
and subsequent relapses unavailable [49];hypnozoites not observed yet [50]Unknown

P. knowlesi

Unknown (gametocytes identified in some of thenaturally infected malaria patients [22])Unknown (hypnozoites not observe [51])Unknown

Sato Journal of Physiological Anthropology(2021) 40:1

environment of the mosquito midgut lumen, and themale and the female gametocytes differentiate to produce microgametes and macrogametes, respectively [52].
The microgamete fertilises the macrogamete to produce
a zygote, the only developmental stage of the parasitethat has a diploid genome [54]. Genetic crossing experiments with gametocytes of two clones of P. falciparumwith different allelic variants demonstrated that recombination can occur in zygotes [55, 56]. Soon the zygote
undergoes meiosis and differentiates into a motile form,
the ookinete, that now contains four haploid genomes in
its nucleus [54]. The ookinete penetrates the wall of themosquito midgut and forms an oocyst on the outer side[57]. In the oocyst, several rounds of mitosis take place,and numerous sporozoites are produced by sporogony[58, 59]. When the oocyst matures, it ruptures, and sporozoites released into the haemolymph migrate to thesalivary glands, where they acquire the ability to infecthuman cells [60] when released into the body of a vertebrate host during a blood meal. Human-infecting Plasmodium species complete this second part of the life
cycle (gametocytes to sporozoites ready to infect thenext person) in around 10–18 days.
Besides the nucleus, the Plasmodium cell has two distinct organelles that contain their own genomic DNA,the mitochondrion and the apicoplast (see below). It has
been shown that each oocyst of P. falciparum developingin the mosquito inherits the mitochondrial genomic
DNA uniparentally from the female gamete [61]. A further study reported that both organellar genomic DNAs
were detected in female gametes of P. gallinaceum (aspecies infecting chickens) but not in male gametes [62].
This suggests that Plasmodium inherits both the mitochondrion and the apicoplast only through the female
gamete (macrogamete).
Recurrence of malaria and the hypnozoite

Malaria can recur after the parasites apparently havebeen cleared from the patient’s blood. Recurrence is due
either to a recrudescence or a relapse (Table 1). Recrudescence originates from a minor population of parasitesthat survived undetected in the patient’s blood, whereas
relapse is caused by cryptic, dormant cells called hypnozoites [43] that persist in the patient’s liver. Hypnozoites
originate exclusively by differentiation from sporozoites
and never from another form of the parasite, such as themerozoites circulating in the patient’s blood [63].
P. vivax is known to produce hypnozoites that cause
relapses after the parasites have been cleared from thepatient’s blood by treatment with antimalarial drugs
such as chloroquine or quinine [12]. There is one report
that, in the majority of relapse cases studied, the genotype of the parasites in the first relapse is different fromthose during the preceding acute episode [64]. This

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result was probably due to the following: (1) P. vivax
sporozoites of two or more different genotypes infecting
a person, (2) sporozoites other than the one that caused
the acute episode differentiating into a hypnozoite in theliver, and (3) only one of those hypnozoites causing therelapse event. External stimuli such as other infections,
including P. falciparum malaria, have been suggested toactivate the hypnozoite and initiate a relapse of P. vivax
malaria [65], although the mechanism has not been
explained.
Of the other human malaria parasites, P. ovale haslong been believed to develop hypnozoites because there
are reports of recurrence without a second infection by
the same species. However, this view has been questioned recently because of a lack of experimental andclinical data unequivocally supporting the presence of
hypnozoites in the liver [49, 50].
Neither P. falciparum nor P. malariae is thought todevelop hypnozoites, and such cells have never been
identified in either species [63]. Nevertheless, these two
species can cause persistent infection without the development of any symptoms over long periods of time. For
example, there is a case report of a P. falciparum infection that persisted asymptomatically in the human bodyfor 13 years [66]. A P. malariae case that most likely
developed after an asymptomatic infection lasted over 40
years has also been reported [47]. Plasmodium parasites
can be maintained in the human blood over long periodsof time at a very low number when their growth rate
and the host’s immunity are able to maintain a subtle
balance. Recurrence (recrudescence) is believed to begin
when the balance is broken.
Whilst there is strong evidence that hypnozoites cause
relapses in P. vivax malaria, some recurrences of P. vivax
malaria might have originated from non-hypnozoite
cells, as in other human malarias [67–69]. Recently, it
was reported that recurrence of parasitaemia had beenrecorded in some neurosyphilis patients who had received a P. vivax malaria patient’s blood for malariotherapy [70–72]. Because P. vivax does not persist as
sporozoites in human blood, no hypnozoite could havedeveloped in the recipients. Thus, these records may
suggest that P. vivax malaria can recur independent of
hypnozoites.
Gametocytes

Throughout development in their vertebrate hosts, Plasmodium cells have a haploid genome. Nevertheless, acloned line of Plasmodium originating from a single cell
generates both male and female gametocytes in the vertebrate host. This indicates that the sex of Plasmodium
gametocytes is not determined chromosomally but epigenetically, and evidence explaining the mechanism isbeing accumulated [38]. The gametocyte sex ratio isSato Journal of Physiological Anthropology(2021) 40:1

apparently affected by environmental factors [73–75],
and this may optimise parasite transmission.
Gametocytes of the Plasmodium species that infecthumans are known to be susceptible to 8aminoquinolines such as primaquine, but not to other
antimalarials such as artemisinin and chloroquine thatkill the parasites in asexual intraerythrocytic development [76]. Thus, even after parasites in their asexual
intraerythrocytic development cycle are removed bytreatment with those antimalarials, transfer of gametocytes in the blood can cause malaria in other people. In
addition, it has been reported that P. falciparum gametocytes can persist for several weeks after the clearanceof asexual blood stage parasites by drug treatment suchas artemisinin-combination therapy [77]. An in vitro
study using culture of gametocytes from one clinical isolate and two laboratory strains of P. falciparum observedthat gametocytes had a 50% survival rate of 2.6–6.5 days
and that surviving cells were detectable until almost 2
months after the start of the experiment [78]. Both therate of clearance of gametocytes from the patient’s bodyand the rate of decline of gametocyte infectivity for mosquitoes depend on multiple factors such as the kind oftreatment and the way it is implemented [79, 80], as well
as host immunity [81]. People with asymptomatic infection can carry a high number of gametocytes in theirblood, just like patients with symptoms of malaria [82–84]. Therefore, gametocytocidal treatment should begiven not only to malaria patients with symptoms but
also to asymptomatic Plasmodium carriers to preventthe parasites in them causing new malaria cases.

Asymptomatic carriers

In areas endemic for malaria, many people carry Plasmodium without developing symptoms because of acquired
immunity [85, 86]. Often, the presence of parasites inthose carriers cannot be detected either by microscopy
or rapid detection tests (RDTs), the two standard tests
for detecting Plasmodium in malaria patients’ blood.
However, infection can be detected with more sensitive
methods, e.g., molecular detection by PCR and LAMP[87], or ultrasensitive variations of RDTs [88]. Asymptomatic carriers can supply infectious gametocytes tomosquitoes, though their impact on malaria in the community where they live may be low or negligible when
the number of gametocytes in the blood is not high [89].
Asymptomatic Plasmodium carriers can develop an episode of malaria when their immunity against the parasite
is compromised, for example, when they move to amalaria-free area where they no longer have new Plasmodium infections that sustain immunity against theparasite. As a result, asymptomatic carriers may cause
imported malaria [90, 91]. Even without developing any

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episodes of malaria, they can also cause transfusion malaria [92] or organ-transplantation malaria [93].
The importance of controlling asymptomatic carriersof malaria parasites in the modern world is higher thanever. It is mainly because people’s movements have become much easier than in earlier times, thanks to economic development and transportation. In addition, thenumber of refugees from regional conflicts, many ofwhich occur in malaria endemic areas, has increased.
Asymptomatic carriers within migrants from malaria endemic areas ought to be identified and adequately caredfor, like patients with apparent malaria symptoms, inorder to prevent the spread or re-introduction of malaria
into malaria-free areas [94, 95].
Apicoplast and plant-like metabolism

The genus Plasmodium belongs to a larger group of protozoans called the Apicomplexa, part of the superphylum Alveolata that also includes dinoflagellates andciliates [96]. Like Plasmodium, almost all apicomplexans
are obligate parasites [31], and many of them, including
all Plasmodium species, have a vestigial, nonphotosynthetic plastid called the apicoplast in the cell
[97–99]. The apicoplast is a secondary plastid surrounded by four layers of membrane [100, 101] and hasa tiny genome, the smallest in size of all known plastid
genomes [102, 103]. Recently, exceptional apicomplexan
species that have a photosynthetic plastid were also discovered [104, 105]. These new species, grouped as chromerids, can grow phototrophically without parasitisingother organisms. The plastids of chromerids containchlorophyll a but lack chlorophyll c that is universallyfound in the plastids of other phototrophic alveolates.
Like the apicoplast, the photosynthetic plastids of chromerids are secondary plastids [106]. Features of theorganellar genome suggest that all apicomplexan plastids
originated from the last common ancestor of present
apicomplexans [107].
Unlike plastids of photosynthetic organisms, the apicoplast is non-photosynthetic, and almost all gene products encoded in the tiny organellar genome are
predicted to be involved in either transcription or translation [108]. Therefore, the reason why parasitic apicomplexans such as Plasmodium carry a non-photosynthetic
plastid was not clear when the organelle’s presence inthe parasite was first recognised [109]. However, as the
genomic information encoded in the nuclear genome ofthe parasites became available [110], it gradually became
evident that the Plasmodium apicoplast is involved inplant-type metabolic pathways including isoprenoid biosynthesis [111], type II fatty acid biosynthesis [112] andhaem biosynthesis [113]. These plant-type pathways involving the apicoplast have been suggested to be important for Plasmodium to complete its development,

Sato Journal of Physiological Anthropology(2021) 40:1

especially in mosquitoes [114, 115] and in the liver [116,117]. However, it has been shown that Plasmodium in
the intraerythrocytic cycle can keep growing in in vitro
culture as long as a sufficient amount of isopentenyl
pyrophosphate (IPP) is supplied in the culture medium,even when they have lost the apicoplast [118]. This suggests that the requirement of the apicoplast for this stageof the parasites is solely to obtain IPP. IPP is the precursor of various isoprenoids and is essential for eukaryotes
including Plasmodium to survive, and the plant-type
methylerythritol phosphate (MEP) pathway in the apicoplast is the only source of this critical molecule in theparasite [119]. One of the enzymes involved in the MEP
pathway, 1-deoxy-D-xylulose-5-phosphate reductoisomerase, is inhibited by a specific inhibitor called fosmidomycin [120], and growth of P. falciparum isinhibited by fosmidomycin both in vitro and in vivo
[121, 122]. By contrast, fosmidomycin does not show asignificant inhibitory effect on the growth of another distantly related apicomplexan Toxoplasma gondii, which
also is supposed to depend on IPP supplied by the MEP
pathway in the apicoplast [123]. The molecular basis of
the resistance of T. gondii to fosmidomycin has beenstudied, and it was suggested that poor drug uptake
through the parasite’s plasma membrane is the cause[124]. Another study suggested that the uptake of fosmidomycin into the erythrocyte which P. falciparum infects
depends on a new permeability pathway induced by theparasite [125]. Although fosmidomycin has good properties as a novel antimalarial [126], Plasmodium may beable to develop resistance to the drug by mutation in unexpected genes.
Some apicomplexans such as Cryptosporidium andGregarina do not have the apicoplast [127], while P. falciparum and T. gondii cannot survive if they lose the organelle [118, 128]. The enzymes involved in the plantlike metabolism in the apicoplast are encoded in the nuclear genome, and apicomplexan species that do nothave the apicoplast tend to lack all the genes specifying
these enzymes [129]. By contrast, the genome of Cryptosporidium species encodes a remarkably large number ofputative amino acid transporters compared to apicomplexans with an apicoplast [130]. These species without
an apicoplast probably acquire the metabolites that ordinary apicomplexans synthesise in the apicoplast, fromthe host using some of those additional transporters.
Antimalarial drugs and resistance

From ancient times, various plant products have beenused in folk medicine to treat malaria. In the seventeenth century, it was shown that the bark of SouthAmerican quina-quina trees (Cinchona spp.) contains anagent with antimalarial activity. This substance, quinine,
has been used in the treatment of malaria since thenPage 6 of 13[131]. In the nineteenth century, efforts began to chemically synthesise pure compounds with antimalarial activity, and some clinically useful synthetic antimalarials
such as chloroquine became available in the 1930s. In
1972, another natural compound used traditionally in
China, artemisinin, was reported to have antimalarial
effect.
Antimalarial drugs currently used in the clinical treatment of human malaria come in five classes based on
their structural backbone and apparent action [132].
Those classes are (1) endoperoxides (e.g. artemisinin andits derivatives), (2) 4-aminoquinolines (chloroquine),aryl-amino alcohols (quinine, mefloquine), (3) antifolates(pyrimethamine, proguanil, sulfadoxine), (4) naphthoquinones (atovaquone) and (5) 8-aminoquinolines (primaquine, tafenoquine). The main targets of inhibition by 4aminoquinolines, anitifolates and naphthoquinones havebeen shown to be detoxification of haem released fromdigested haemoglobin, pyrimidine biosynthesis andmitochondrial cytochrome b involved in oxidoreduction,
respectively. Aryl amino alcohol class inhibitors seem toinhibit the same metabolism as 4-aminoquinolines,
whereas endoperoxides, such as artemisinin, act on multiple cellular processes involving reactive oxygen species
in Plasmodium cells.
The parasites causing human malaria, especially P. falciparum, have acquired resistance to each of these antimalarials one by one, and today, drug-resistant parasites
are prevalent in malaria endemic areas [133]. It has been
well documented that point mutations causing aminoacid substitutions in the active site of dihydrofolate reductase (the target enzyme of pyrimethamine and proguanil) make P. falciparum highly resistant to thoseantifolate drugs [134, 135]. Another example includes
specific point mutations occurring in pfcrt and pfmdr1,
which specify transporters CRT and MDR1, respectively,
which promote the efflux of antimalarials such as 4aminoquinolines and aryl amino alcohols from the digestive vacuoles of P. falciparum [136]. As a result, parasites with these mutated genes become resistant toantimalarials that block haem detoxification in the digestive vacuoles. Point mutations in a gene are not the
only the way for the parasites to acquire resistance toantimalarials. For example, when expression of the affected gene product is elevated because of gene amplification or a change in regulatory mechanisms,
antimalarials can reduce or lose their efficacy [137, 138].
It is also potentially possible that Plasmodium species
acquire new machinery with which the parasites can survive without the metabolism targeted by an antimalarial.
For example, if Plasmodium acquires a new transporter
with which they can acquire IPP from the host, as
Cryptosporidium species can, the parasites become resistant to fosmidomycin.

Sato Journal of Physiological Anthropology(2021) 40:1

It has been reported that clinical isolates of P. falciparum showing resistance to multiple antimalarial drugs
tend to have defects in DNA mismatch repair [139, 140].
Genetic changes are often harmful, so having defects in
DNA mismatch repair, which causes a higher rate ofgenetic changes in the genome, can reduce the fitness ofthe parasites affected. However, parasites with such defects have a potential to generate a wider variety of genetic changes compared to those without such defects.
This is presumably beneficial for the parasites in orderto survive under strong drug pressure. The A + T content of the genome of Plasmodium species is generallyhigh (> 60%); it is especially high in the genome of P. falciparum—nearly 80% in coding regions and approaching
90% in non-coding regions. The genome of P. falciparum has been shown to be prone to small genetic
changes such as indel mutations [141]. The high A + T
content of the genome may also contribute to Plasmodium developing drug resistance.
Host specificity

The natural host range of Plasmodium depends on thespecies. It can be extremely narrow as in P. falciparum,
which infects humans but not African apes that are
phylogenetically very close to humans [142]. The range
can also be very wide as in P. relictum, which is known
to infect more than 100 different species of birds aroundthe world, classified into different families and orders[143]. Traditionally, Plasmodium species are subcategorised into distinct subgenera based on theirmorphology and ranges of vertebrate hosts and vectors[32]. It has been pointed out that the genus Plasmodium
as a whole is polyphyletic and that the taxonomy of theorder Haemosporidia, which consists of Plasmodium
and other related genera, has many conflicts [144].
Nevertheless, each subgenus of Plasmodium seems to bemonophyletic. Plasmodium species that infect mammals
generally belong to either one of three subgenera, Laverania, Plasmodium or Vinckeia, apart from some species
recently identified from ungulate hosts [32, 144, 145].
The subgenera Laverania, Plasmodium and Vinckeia
consist of parasite species that infect apes, monkeys androdents, respectively.
Unlike Plasmodium species that infect birds, which aretransmitted by a wide variety of mosquitoes including
Culex and Aedes, mammalian malaria parasites belonging to subgenera Laverania, Plasmodium and Vinckeia
are transmitted only by anopheline mosquitoes [32].
This is because mammalian Plasmodium species cancomplete their development from gametocytes to infectious sporozoites only in anopheline mosquitoes. However, this does not mean that these parasites cannot
developmentally differentiate from gametocytes in nonanopheline mosquitoes [146]. There was an early report

Page 7 of 13

that oocysts formed on the midgut epithelium, and sporozoites were observed in the salivary gland when Culex
bitaeniorhynchus was fed with human blood containing
gametocytes of P. falciparum or other human malaria
parasites [147]. However, another recent study reported
that a laboratory strain of P. falciparum fed to C. quinquefasciatus developed ookinetes that soon lysed andnever formed oocysts [148]. This suggests that P. falciparum is killed by the mosquito’s immune system when
the ookinetes are exposed to the haemolymph of nonanopheline mosquitoes [149].
It is not true that all anopheline mosquitoes areequally important in transmitting Plasmodium between
humans or animals; different Anopheles species have different habitats, feeding behaviour and preference for the
animal species from which they suck blood [150]. These
differences may promote species differentiation in theparasites they carry and provide a chance for the parasite
to switch its host [151].
Of the four human Plasmodium species, P. falciparum
belongs to subgenus Laverania, whereas all the others
belong to subgenus Plasmodium. P. knowlesi that causes
zoonotic malaria in humans also belongs to the subgenus Plasmodium. Generally, P. falciparum only infects
humans in natural conditions [152], though it is possible
to adapt the species to infect chimpanzees in the laboratory [153]. Krief et al. reported that they isolated P. falciparum from bonobos (Pan paniscus) kept at the Lolaya Bonobo Sanctuary in the Democratic Republic of theCongo, though the mitochondrial haplotype map they
drew indicated that the isolates from bonobos were genetically distant from P. falciparum parasites infecting
humans [154]. The non-P. falciparum Laverania species
that is phylogenetically closest to P. falciparum is P.
praefalciparum, which infects gorillas but not humans
or chimpanzees [152]. As with these two species, all
Plasmodium species of subgenus Laverania so far described show a strong host specificity in their naturaltransmission [152, 155]. A longitudinal survey of anopheline mosquitoes carried out in two wildlife reserves in
Gabon where different Laverania species coexist revealed that the three sylvan Anopheles species collectedin the survey, An. vinckei, An. moucheti and An. marshallii, carried multiple Laverania species whose vertebrate host specificity varied [151]. This indicates that thestrong host specificity of the Laverania species is not
solely caused by specific association between anopheline
vectors and vertebrate hosts. A recent comparative genomics study between Laverania species revealed thatthese parasites have striking copy number differences
and structural variations in multiple gene families intheir genomes [156]. Variations in the stevor family,
which has been shown to be involved in host-parasite interactions in P. falciparum [157], showed a host-specificSato Journal of Physiological Anthropology(2021) 40:1

sequence pattern. Probably these variations are criticallyimportant for each Laverania species to determine theirstrong host specificity. Rh5, a member of another genefamily, has been shown to be important for Plasmodium
species of subgenus Laverania to bind to erythrocytes of
specific hosts [158]. EBA165, a member of the erythrocyte binding-like (EBL) gene family, is pseudogenised in
the genome of P. falciparum but not in other Laverania
species’ genomes. A recent study showed that P. falciparum becomes capable of binding to ape erythrocytes
but loses the ability to bind human erythrocytes when afunctional EBA165 product is expressed [159]. This suggests that losing the functional EBA165 product was a
key step in the emergence of the human-infecting P. falciparum from its P. praefalciparum-like ancestor thatprobably did not infect humans.
In the mosquito survey in Gabon described above, it
was also found that the three sylvan species of Anopheles carried Plasmodium species which were extremely
close to P. vivax or P. malariae [151]. In a phylogenetic
analysis, these P. vivax-like isolates from mosquitoes collected in the survey in Gabon made a cluster with P.
simium, one of the two South American zoonotic Plasmodium species [151]. Another study suggested that P.
brasilianum, the other South American zoonotic Plasmodium, is probably an amphixenotic variant of P.
malariae that acquired infectivity to the simian hosts
while also keeping its original human infectivity [29]. All
these suggest that both P. vivax and P. malariae canswitch their host more easily than the species of subgenus Laverania [151]. However, the mechanisms behind host switching of species of subgenus Plasmodiumincluding P. knowlesi and other simian species causing
zoonotic malaria are not well understood.

Conclusions
Humans have long suffered from malaria, the diseasecaused by Plasmodium. Thanks to the discovery of natural and chemically synthesised antimalarials, malaria
has become a disease curable by chemotherapy. Together with mosquito vector control using insecticides,
treatment of malaria patients with synthetic antimalarials
such as chloroquine and artemisinin has dramatically reduced the burden of malaria in the modern world compared to the past. Nevertheless, malaria is still prevalent,
killing hundreds of thousands of people globally every
year.
One of the problems that hinder control of malaria isthe emergence and spread of chemotherapy-resistantparasites [160–162]. To solve this problem, novel antimalarial substances whose targets are different fromthose of existing antimalarials are sought. Using thoseinhibitors in combination with existing antimalarials
largely reduces the risk that the parasites acquire

Page 8 of 13

resistance to each substance. For example, inhibitors of
the plant-like metabolic pathways of the parasite are
attracting attention.
Another problem is that Plasmodium can be easily
carried from endemic areas to non-endemic areas in themodern world because of increased movement of people.
Malaria-free countries and areas are steadily increasing,but imported malaria is a commonly shared threat
against health in many countries and areas. Plasmodium
species can be retained in the human body for a longtime without causing any overt symptoms. Asymptomatic Plasmodium carriers can start developing malaria
spontaneously and spread imported malaria in malaria
non-endemic countries and areas. These people may also
spread the parasite when they are involved in bloodtransfusions and organ transplantation as donors.
P. falciparum and other human-infecting Plasmodium
species share a characteristic that lets them infecthumans, which is the outcome of convergent evolution.
Currently, Plasmodium species that naturally cause malaria in humans are limited, but other species may alsoacquire natural infectivity to humans and start causing
new zoonotic malaria at any time. The physical distance
between humans and non-human animals such as otherprimates can depend on the degree of local development, and this could affect the chance of non-human
Plasmodium species becoming the cause of zoonotic
malaria in humans.
Plasmodium species may change their insect hosts aswell. Unlike the Plasmodium species that infect mammals, avian malaria parasites develop and produce infectious sporozoites in non-anopheline mosquitoes. Thisimplies that mammalian Plasmodium species also could
acquire resistance to the immune system of nonanopheline mosquitoes such as Culex and Aedes and use
them as transmission vectors. Some non-anophelinemosquito species can breed even in harsh environments
such as in tunnels, on the coast or in urbanised areas,and can be cosmopolitan [163, 164]. If a Plasmodium
species that can cause malaria in humans acquired thecapability of completing its mosquito stage development
in non-anopheline mosquitoes, its impact on human society could be substantial.
The relationship between humans and Plasmodiumchanges dynamically due to both the parasites’ natureand the activities of humans. Understanding the basic
biology of the parasites that leads to these changes, andapplying the knowledge to malaria control, should help
to achieve a healthier global society.
Abbreviations
ITN: Insecticide-treated bed net; NMCP: National Malaria Control Programme;
RDT: Rapid detection test; IPP: Isopentenyl pyrophosphate;
MEP: Methylerythritol phosphate

Sato Journal of Physiological Anthropology(2021) 40:1

Acknowledgements
The author thanks Iain Wilson and Tony Holder for careful reading of themanuscript.
Author’s contributions
SS wrote the manuscript. The author read and approved the final
manuscript.
Funding
Not applicable.
Availability of data and materials
Not applicable.
Ethics approval and consent to participate
Not applicable.
Consent for publication
Not applicable.
Competing interests
The author declares that they have no competing interests.
Received: 11 September 2020 Accepted: 21 December 2020

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