MEDITERRANEAN JOURNAL OF HEMATOLOGY AND INFECTIOUS DISEASES

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Review Articles

Biology off Human Malaria Plasmodia Including Plasmodium Knowlesi

Spinello Antinori, Laura Galimberti, Laura Milazzo and Mario Corbellino

Department of Clinical Sciences L. Sacco, Section of Infectious Diseases and Immunopathology, University of
Milano, Italy

Correspondence to: Spinello Antinori, Department of Clinical Science L Sacco, Section of Infectious Diseases and
Immunopathology, Università degli Studi di Milano, Via GB Grassi 74, 20157, Milano, Italy. Tel: +39-02-
50319765, Fax: +39-02-50319768. E-mail:
mail: spinello.antinori@unimi.it

Competing interests: The authors have declared that

th no competing interests exist.

Published: March 10, 2012

Received: January 9, 2012
Accepted: February 11, 2012
Mediterr J Hematol Infect Dis 2012, 4(1): e2012013,
e201 DOI 10.4084/MJHID.2012.013
This article is available from: http://www.mjhid.org/article/view/9883
This is an Open Access article distributed under the terms of the Creative Commons Attribution License
(http://creativecommons.org/licenses/by/2.0
http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium,
provided the original work is properly cited.
cited

Abstract. Malaria is a vector-borne borne infection caused by unicellular parasite of the genus
Plasmodium. Plasmodia are obligate intracellular parasites that are able to infect and replicate
within the erythrocytes after a clinically silent replication phase in the liver. Four species
(P.falciparum, P.malariae, P.ovale and P.vivax)) are traditionally recognized as responsible of
natural infection in human beings but the recent upsurge of P.knowlesi malaria in South
South-East Asia
has led clinicianss to consider it as the fifth human malaria parasite. Recent studies in wild
wild-living
apes in Africa have revealed that P.falciparum,, the most deadly form of human malaria, is not only
human-host
host restricted as previously believed and its phylogenetic lineage is much more complex
with new species identified in gorilla, bonobo and chimpanzee. Although less impressive, new data
on biology of P.malariae, P.ovale and P.vivax are also emerging and will be briefly discussed in this
review.

Introduction. Four host-restricted

restricted or adapted species phylum Apicomplexa with an evolution from the
of Plasmodium are traditionally recognized as Coccidiann stem that encompass the progressive
responsible of human malaria: Plasmodium falciparum,
falciparum acquisition of more complicated phases in their life life-
P.malariae, P.ovale and P.vivax.1 Occasionally, human cycles confined to a single host . Finally, the successful
beings can be infected either naturally or accidentally survival of these parasites requires completion of life
by several simian species such as P. cynomolgi cycle in two alternative hosts of evolutionarily ddistant
cynomolgi, P.cynomolgi bastianelli,
bastianelli P.simiovale, species (i.e. human and mosquito).The genus
P.knowlesi 1 The
P.brasilianum, P.schwetzi, P.inui and P.knowlesi. Plasmodium is subdivided in the sub sub-genus
latter emerged as an important
nt cause of human malaria Plasmodium and Laverania within the sub-order
in South-East
East Asia, especially the Malaysian Borneo Haemosporidiidea (Table
Table 11).
since 2004 and will be discussed together with the Plasmodium contains three genomes: 1) a nuclear
other human plasmodia.2 genome that comprises 14 linear chromos
chromosomes;2) a
Plasmodia have been regarded as belonging to the linear mitochondrial genome that is one of the smallest

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Table 1. Classification of human protozoa of the genus myosin motor system. The tissue phase extinguishes
Plasmodium itself at this point with the notable exception of P.vivax
Domain Eukaryota and P.ovale (and certain other primate species such as
Kingdom Chromalveolata P.cynomolgi) who are able to persist in the liver as
“hypnozoites” that are eventually responsible of the
Superphylum Alveolata
phenomenon of relapse. The blood cycle begins when
Phylum Apicomplexa the merozoites invade the erythrocytes and the period
Class Aconoidasida of time from the infection by mosquito bite and the
Order Haemosporida first appearance of the trophozoites in the erythrocytes
Sub-order Haemosporidiidea is called “prepatent period” ; this period is
Family Plasmodiidae characteristic of each species and is constant. The
prepatent period lasts 9 days in P.falciparum, 11-13
Genus Plasmodia
days in P.vivax, 10-14 days in P.ovale, 15 days in
Sub-genus Plasmodium; Laverania
P.malariae and 9-12 days in P.knowlesi (Table 2).
P.falciparum
Within the erythrocytes, trophozoites mature over the
P.malariae
Species P.ovale course of 24-72 hours, a phenomenon that is again
P.vivax species-dependent, with the production of blood-
P.knowlesi* schizonts each one containing 6 to 36 merozoites. The
* P.knowlesi is a primary parasite of monkey that can infect rupture of erythrocytes releases into the blood a new
humans
wave of merozoites that are able to infect other
known ; 3) a 35 kb circular plastid genome of red-algal erythrocytes. The rupture of the schizonts is followed
origin, that is housed in the apicoplast. by the appearance of the malaria febrile paroxysm
The life cycle of all species of human malaria classically lasting 8 to 12 hours ( “Golgi cycle”) and
parasites is characterized by an exogenous sexual characterized by three stages : 1) the cold stage marked
phase (named sporogony), in which multiplication by the rapid rise of the temperature associated with
occurs in several species of Anopheles mosquitos, and chills; 2) the hot stage with the temperature peak , skin
an endogenous asexual phase (named schizogony) vasodilatation, headache, myalgias; 3) the sweat stage
which take place in the vertebrate host.1 The latter with defervescence. However, it should be noted that
phase begins when sporozoites following the the appearance of typical febrile periodicity (tertian or
inoculation by mosquito, enter the parenchymal cells of quartan fever) requires the synchronization of the
liver, and undergo their development and blood parasite cycles and since symptomatic cases of
multiplication , a process that is known as , pre- malaria are usually observed earlier than in the past,
erythrocytic schizogony. In the vertebrate host the life this feature is now rarely encountered in the clinical
cycle of Plasmodium is characterized by a tissue phase practice in western countries. During the process of
in the liver, followed by a blood phase, that is schizogony some of the merozoites differentiate into
ultimately responsible of the appearance of clinical sexual forms- female (macrogametocytes) and -male
manifestations. It is generally believed that once an (microgametocytes), respectively, which are
infectious female anopheline mosquito injects responsible, if ingested by a female anopheline
sporozoites in the blood, they are able to travel quickly mosquito of the definite sporogonic cycle. It was
to the liver where they invade the host’s hepatocytes. initially believed that gametocytes persisted in the
However, new findings seems to indicate the existence blood for long periods of time but, a study by Hawking
of a more complex invasion process characterized by and coworkers ,conducted on P.knowlesi, P.cynomolgi
the persistence of sporozoites in human dermis for and P.cathemerium (a duck Plasmodium) contrasted
hours with a slow release into capillaries as well as this view.5 They showed that gametocytes develop to
migration through lymphatic system.3,4 In the liver the the stage of infectivity for mosquitoes a few hours
sporozoites undergo their replication becoming a tissue longer than their asexual cycle and then remain mature
schizont that contains thousands of merozoites (about for only a short period of hours (5-12) finally
10,000 in P.vivax/P.ovale and up to 30,000 in degenerating and disappearing from the blood. The
P.falciparum). This exoerythrocytic schizogony is molecular mechanism that triggers the development of
characteristic of each species and takes a minimum gametocytes as well as the factors that determine the
maturation time of 6 days in P.falciparum and a sex of gametocytes are poorly understood; however,
maximum of 16 days in P.malariae. The mature duration and stages of gametocytogenesis vary among
schizont ruptures (together with the infected Plasmodium species.
hepatocytes) releasing merozoites that once in the The sexual development of malaria parasite
blood actively invade erythrocytes using an acto- (sporogonic cycle) will be completed only when

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Table 2. Characteristics of infection with the five species of Plasmodia infecting humans

Plasmodium
Characteristics P.knowlesi P.malariae P.ovale P.vivax
falciparum
Pre-erythrocytic stage
5-7 8-9 14-16 9 6-8
(days)
Pre-patent period (days) 9-10 9-12 15-16 10-14 11-13
Erythrocytic cycle (days) 48 24 72 50 48
Red cells affected All All Mature erythrocytes Reticulocytes Reticulocytes
Parasitaemia per µL
 Average 20,000-500,000 600-10,000 6000 9000 20,000
 Maximum 2,000,000 236,000 20,000 30,000 100,000
Febrile paroxysm (hours) 16-36 or longer 8-12 8-10 8-12 8-12
Severe malaria Yes Yes No No Yes
Relapses from liver forms No No No Yes Yes
Yes (as long as 30-50
Yes (treatment Yes (treatment
Recurrences Yes years after primary No
failure) failure)
attack)

mature female and male gametocytes are ingested by a variable (7-30 days), characteristic of each species and
biologically suitable species of female Anopheles influenced by ambient temperature. Oocyst
mosquito during a blood meal. A mosquito blood meal development is the longest developmental phase as
is, on average, 2 to 3 µL, and should contain at least well as the only extracellular of the Plasmodium life
one male and one female gametocyte to be infective. cycle. The sporozoites actively escape from the oocyst
Host location by the mosquito is mediated by and only 25 % of those liberated by oocyst migrate
physical (heat, moisture, visual) and chemical cues that through the hemocoelomic fluid to the acinal cells of
play a role during orientation and landing. 6,7 It is salivary glands, where after about a day of residence,
known that skin bacteria play an important role in the they became highly infective.10 They are irreversibly
production of human body odour and convert non- programmed for their journey in the vertebrate host
volatile compounds into volatile compounds with because they completely lost their capacity to re-infect
characteristic smells. In a recent elegant experiment salivary glands.10 Once that the mosquito bites the
Verhulst et al. studied the attractiveness of 48 human piercing proboscis probes the dermis for a blood vessel
males to Anopheles gambiae (a nocturnal highly and ejects saliva, which, via its anticoagulant activity,
anthropophilic species) one of the major malaria vector facilitates blood ingestion.11 Sporozoites present in the
in Africa. They showed that individuals with higher salivary ducts are ejected during skin probing in a
skin microbial diversity and higher abundance of number generally not exceeding 10-100.
Pseudomonas and Variovorax spp. were less attractive
to the mosquitoes and hypothesized an in-built defence Plasmodium falciparum. Plasmodium (Laverania)
system controlled by the Major Histocompatibility falciparum (Welch, 1896) is the highly pathogenic and
Complex genes.8 most deadly parasite causing malaria in humans. It was
Once in the midgut of the insect the discovered in 1880 by Charles Alphonse Laveran, a
macrogametocyte (i.e. female) is released by the French Army Surgeon, deployed in Constantine
erythrocytes to became a macrogamete (within 5 (Algeria) and originally named by himself Oscillaria
minutes) whereas the male counterpart malariae.12 Examining under a microscope a drop of
(microgametocyte) divides its nucleus more slowly blood from a young soldier with fever, Laveran
(about 20 minutes) into eight flagellated microgametes observed some spherical and crescent-shaped bodies
responsible of the fertilization of macrogamete a with actively moving filaments ; he was looking at
process that takes one hour.9 The zygote that is formed exflagellation of a male gametocytes of P.falciparum a
by the fusion of the two nuclei evolved into a slowly phenomenon that was subsequently explained by
motile ookinete that actively penetrate the peritrophic Maccallum.13 Exflagellation of the microgametocyte in
membrane and the midgut epithelium. Twenty-four to the life cycle of malarial parasites occurs in the
forty-eight hours after the ingestion of blood, the stomach of mosquitoes after ingestion of an infected
oocyst develops and, subsequently, its single nucleus blood meal but in rare cases it can be observed also in
divides repeatedly until the formation of a mature the peripheral blood smear of infected humans,
oocyst that contains thousands of sporozoites. The time generally as the consequence of extended delay in slide
span required to development of mature oocyst is quite preparation or following warming.14
Mediterr J Hematol Infect Dis 2012; 4: Open Journal System
 Eighty-five countries are actually classified as P.falciparum erythrocyte membrane protein 1
endemic for P.falciparum malaria with 2.57 billion (PfEMP1) that is known to be encoded by about 60
people living in area at risk for transmission of this members of the specific var gene family, is considered
infection.15 Of these, 1.44 billion people live in area of the principal virulence factor of P.falciparum because
stable transmission, mainly in Africa (52% of the PfEMP1 proteins, expressed on the surface of infected
global total) and Central, South and East Asia (46%).16 erythrocytes, are able to mediate adhesion to both
The estimate of the burden of P.falciparum clinical uninfected and host endothelial cells.19
malaria is a difficult task complicated by several The exoerythrocytic schizogony of P.falciparum is
factors such as inadequate and incomplete national a rapid process that is usually completed in five and
reporting systems and inaccurate diagnoses with half days with the production of a schizont,
possible overestimate disease rates. By using improved characterized by bizarre forms, containing a very high
cartographic and epidemiological data sources number of merozoites. Following the rupture of liver
combined with geostatistical space-time joint schizonts, each released merozoite invade an
simulation framework, Hay and coworkers, estimated erythrocyte a complex process that requires a
that in 2007 there were 451 (95 % confidence interval recognition between receptors (on erythrocyte) and
349-553) million clinical cases of P.falciparum ligands (on merozoite). In the case of P.falciparum,
malaria.17 Sixty percent (271 million) occurred in early studies identified as possible receptors for
Africa (including Saudi Arabia and Yemen), and 39 % merozoite invasion sialic acid, glycophorin A, B and
in the 19 countries of Central and South East (CSE) C.23-25 Another sialic acid-independent erythrocyte
Asia with the highest-burden countries being Nigeria receptor for P.falciparum adhesin PfRh4, the
and Democratic Republic of Congo in Africa and India complement receptor 1 (CR1) has been identified in
and Myanmar in CSE Asia region.16 These figures are 2010.26 However, none of these receptor-ligand pairs
in contrast with the most recent estimates by the WHO were shown to be essential in all parasite strains tested.
that reported in 2010 an estimated 216 million (149- More recently, Crosnier and colleagues identified
274 million) episodes of malaria worldwide with basigin, an antigen of the Ok blood group , as the
655,000 deaths (537,000-907,000).18 receptor essential for the erythrocyte invasion by
The whole genome of P.falciparum has been P.falciparum.27 Basigin is also known as CD147,
sequenced and published in 2002 being a major EMMPRIN and M6 and is a member of the
advance in the struggle against this lethal parasite.19 immunoglobulin superfamily (IgSF) that is implicated
The nuclear genome, distributed in 14 linear in many biological functions. In more detail, basigin
chromosomes, consists of about 5,365 genes of whom proved to be a receptor for the PfRh5 a unique protein
1,817 have known functions (Table 3). Of these 1,817 among the EBAs and Rhs that cannot be deleted in any
functional genes of P.falciparum, 81.6 % have been P.falciparum strain.27
shown to be conserved with those of P.vivax and only Erythrocytic schizogony is characterized by the
334 genes (18.5%) were unique to the former species.20 appearance in the blood of young rings whereas the
In comparison with P.vivax and P.knowlesi genomes, maturation stages are rarely seen in the peripheral
P.falciparum shows an higher content of A+T and blood. There is no enlargement of the infected
despite having the smallest genome size it displays the erythrocytes during the development and the mature
highest content of simple sequence repeats (SSRs) that schizont usually contains 8-32 merozoites. The
are supposed to be responsible of genome complexity gametocytes of P.falciparum develop in the internal
responsible for rapid evolutionary adaptation (Table organs and do not appear until about eight to ten days
3).21 The proteomic characterization of the four stages after the start of parasitaemia. P.falciparum
of the parasite life cycle (sporozoite, merozoite, gametocytogenesis has been characterized through five
trophozoite, gametocyte) showed that about half of the morphologically distinct substages.28,29 Immature
sporozoite proteins are unique to this stage whereas P.falciparum gametocytes (stage I-IV) are sequestered
trophozoite, merozoite and gametocytes had between away from circulation and only the mature crescent-
20 % and 30 % unique proteins.22 Moreover only 152 shaped gametocytes (stage V) are released in
proteins (6%) were shared to all four stages and the peripheral blood where they finally become infectious
high degree of proteome diversity of each stage of the to mosquitoes.29
Plasmodium life cycle suggested a highly coordinated Until the last year, the closest ancestor of
expression of genes involved in common process. P.falciparum was considered to be a chimpanzee
However, the comparative genomics analyses of parasite, P.reichenowi, which was believed to have
Plasmodium genomes indicated the genes mediating diverged from its human counterpart 5-7 Myears.30-32
parasite-host interactions are frequently restricted to a However, a recent paper, published in 2010 , in whom
single Plasmodium species. For P.falciparum, the the Authors analyzed more than 2500 samples of ape

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Table 3. Comparative genome size , whole genome SSR , A+T and G+C content of the three sequenced genome of Plasmodium species
causing human malaria

Overall genome Number of Overall SSR Overall A+T Overall G+C content
Plasmodium species
size (Mb) genes* content (%) content (%) (%)
Plasmodium vivax 26.8 5,433 3.8 58 42.3
Plasmodium knowlesi 23.5 5,188 4.92 63 37.5
Plasmodium falciparum 23.3 5,403 10.5 81 19.4
*
Including pseudogenes and partial genes, excluding non-coding RNA genes; SSR=simple sequence repeats; A=adenine; T=thymine;
G=guanine; C=cytosine

fecal material as a source of Plasmodium DNA, using a represents the most GC-rich (42.3 %) Plasmodium
single-genome amplification strategy, challenged this genome sequenced to date (Table 3). A recent analysis
view.33 The Authors, claimed that human P.falciparum of proteome of P.vivax was able to identify 7 proteins
sequences constitute a single lineage nested within the which were entirely specific to P.vivax and 16 proteins
G1 clade of gorilla parasites thus suggesting that that did not share any homology in P.falciparum (2 Vir
human P.falciparum is of gorilla origin and not of and 8 P-fam proteins) probably implicated in
chimpanzee.33,34 Moreover, several papers published in virulence/antigenicity of P.vivax.46
2010, showed that P.falciparum, once considered Plasmodium vivax is present throughout the tropics
strictly human specific, can infect bonobos, with low rate of infection in western and central sub-
chimpanzees and gorillas and thus these African apes Saharan Africa. According to recent estimates 40% of
might serve also as possible reservoir for the malignant the world’s population (2.6 billion people) is at risk of
form of human malaria.35-38 In this regard, five new P.vivax transmission with between 130-435 million
phylogenetic species within the Laverania subgenus clinical episodes of vivax malaria each year.47,48 The
have been identified in just one year providing a new origin of P.vivax has been , as in the case of
representation of the phylogeny with two groups. P.falciparum, a debatable question with different
Group A that includes three species : P.GorA (that hypotheses; the abundance of simian malaria species
infects Gorillas), P.gaboni and P.billbrayi (both observed in Southeast Asia together with
infecting chimpanzees) and group B that includes morphological and biological characteristics shared by
P.falciparum and P.reichenowi and P.GorB (that P.vivax with macaque parasites where the arguments
infects gorillas) and P.billcollinsi (that infects used to place the origin of P.vivax in Southeast Asia.49
chimpanzees).39 Finally, researchers from USA, On the contrary, the high prevalence of Duffy
confuted the new view that P.falciparum was negativity (i.e. the lack of the Duffy blood group
transferred by gorilla to human and on the basis of their antigen) among human population throughout sub-
analysis of 45 orthologous gene sequences , indicated Saharan Africa has been indicated to argue an African
that ape infections with P.falciparum might be a very origin for P.vivax 50 Subsequent studies using data
recent phenomena.40 regarding complete mitochondrial genomes and
nuclear and plastid genes argued that P.vivax was
Plasmodium vivax. Plasmodium vivax (Grassi and introduced into Homo sapiens in Asia by a species of
Feletti, 1890) is responsible of the so called “benign Plasmodium parasitic to macaques.51-53
tertian fever” although the lack of life-threatening Sporozoites of P.vivax, once in the liver,
complications associated with this infection have been differentiate either into early, primary tissue schizonts
recently questioned by several reports.41,42 It was or into hypnozoites which are responsible for late
identified as a separate malaria parasite together with relapse of the infection. The term “hypnozoite” was
P.malariae in 1886 by Camillo Golgi who described probably coined and adopted for malaria by Markus in
the typical “tertian” and “quartan” fever paroxisms and 1978 whereas the biological proof of the existence of
confuted the Laveran’s postulate of the existence of a hypnozoites is the direct consequence of the work by
single malaria species.43 In 1890 Giovan Battista Krotoski and coworkers.54-56
Grassi and Raimondo Feletti named them The biological determinant that supports the active
Haemamoeba vivax and H.malariae.44 The whole or dormant development pathway is still unknown
genome of P.vivax Salvador I strain was sequenced and although the relapsing nature of P.vivax malaria was
published in 2008: with its 26.8-megabase (Mb) described at the end of nineteen century by Thayer,
nuclear genome is higher than that of P.falciparum and Bignami and Manson as outlined in the recent elegant
displays chromosomes that are unique among human review by White.57
Plasmodium species with an isochore structure.45 It During the erythrocytic development of P.vivax all
contains 5,433 predicted protein coding genes and forms can be found in the peripheral blood and in most

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stages the appearance is larger that in the other species seasonal stimuli or mosquito bites, have been
of human Plasmodia. It is also responsible of the proposed.57,64
enlargement of host cells thus increasing its In the Anopheles mosquito, after fertilization the
deformability.1 The parasite preferentially invades sexual cycle takes 8-10 days at 28 °C and 16 days at 20
young red blood cells (i.e reticulocytes) an issue that °C whereas below 15 °C the completion of the
seems to limit its reproductive capacity with level of sporogonic cycle is unlikely.1
parasitaemia that rarely exceed 2 % of circulating
erythrocytes. The invasion of erythrocytes by P.vivax Plasmodium ovale. Plasmodium ovale (Stevens, 1922)
merozoites requires interaction with the Duffy antigen was discovered in 1922 by Stephens who observed it in
receptor for chemokines (DARC) with Duffy-negative the blood of an East african patient with malaria
individuals considered to be naturally resistant to this erythrocytes with oval shape and fimbriated edges and
human malaria parasite.58 The high proportion of named the parasite P.ovale.66 Using the sequences of
Duffy-negative people in West and Central Africa has the small subunit ribosomal RNA (SSUrRNA) gene it
long be viewed as the most plausible explanation of the has been established that P.ovale belong to 2 genetic
rarity of P.vivax malaria in those geographical areas. haplotypes named classic and variant.67 Both the
However, in recent years several investigators either in classical and variant types are morphologically
Africa and South America were able to demonstrate indistinguishable and occurred in sympatry worldwide
that P.vivax has evolved and adapted in a way that ; based on the observation that no evidence of inter-or
circumvent this pathway and it is able to invade intragenic recombination could be observed among
erythrocytes also in individuals who lack the Duffy samples coming from different part of the world,
antigen on their red cells.59-61 The young throphozoite Sutherland and coworkers raised the possibility of the
grows rapidly and exibits the characteristic malaria existence of 2 species and proposed to name these
pigment; subsequently it assumes an amoeboid activity species P.ovale curtisi (classic type) and P.ovale
and a large vacuole forms a “hole” within the ring until wallikeri (variant type) in honour of 2 malariologists :
the division of the nucleus begins. The mature schizont Christofer Curtis (1939-2008) and David Walliker
contains on average 12 to 18 merozoites and fills the (1940-2007).68,69 P.ovale is distributed in sub-Saharan
entire host cell.1,49 Africa, South-east Asia (Philippines, Myanmar,
Gametocytes production probably start with the first Vietnam, Thailand) , Middle East, the Indian
generation of merozoites of P.vivax and can be subcontinent, Papua New Guinea and Irian Jaya and
detected within 3 days after the first asexual parasites East Timor in Indonesia ; it has never been reported
are observed.29 from South America.70 It has been estimated that the
One of the most intriguing and debatable issue global burden of P.ovale in Africa might exceeds 15
regarding P.vivax is whether or not it exists as a single million cases annually.68 The prepatent period (i.e. the
species or on the contrary different species or sub- interval between sporozoites inoculation and the first
species are represented.62-64 Li and coworkers showed detection of parasites in peripheral blood) of P.ovale is
that P.vivax comprises two distinct lineages with between 12 and 20 days , with a median of 14,5 days.71
phenotypic difference with respect to their preferred Parasitaemia is usually low during P.ovale infection
mosquito vector and with a distinct chromosomal probably as the consequence of restricted development
translocation.65 On the basis of differences on the in younger erythrocytes; in a study regarding 90
incubation period and on relapse intervals it has been patients the maximum parasite levels ranged between
known for a long that different phenotypes (P.vivax 380 and 27,660/µL with a mean maximum parasite
Chesson, P.vivax Madagascar,St.Elizabeth, P.vivax level of 6,944/µL.71 The changes produced by P.ovale
North Korean, P.vivax Hibernans) are responsible of on the infected erythrocytes are similar to those seen in
different presentation.62,63 Madagascar and St.Elizabeth P.vivax whereas the schizonts and gametocytes may
strains (considered the typical P.vivax) usually cause a resemble those of P.malariae.1 The completion of the
primary illness two weeks after mosquito inoculation sporogonic cycle in the mosquito takes 12-14 days at
with subsequent relapse after an interval of 7-10 28 °C.
months but with shortened subsequent inter-relapse P.ovale is generally regarded as responsible of a
intervals. On the contrary the P.vivax hibernans relapsing infection originating from dormant
(distributed in northern Europe and Russia) presented a (“hypnozoites”) exo-erythrocytic stages in the liver.1,71
primary infection 8-10 months after inoculation. According to Collins and Jeffery, the only
Finally , the P.vivax Chesson strain shows very demonstration of the existence of liver hypnozoites in
frequent relapses and high relapse rate. The exact human was that of Garnham and coworkers who made
trigger for the activation of hypnozoites is not a liver biopsy in a volunteer that was deliberately fed
understood and various theories such external stresses, by Anopheles mosquitoes infected with a Liberian

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strain of P.ovale.71,72 However, in a recent provocative more than 30-40 years or longer.1,78-80 Moreover,
article by Richter and colleagues, the Authors reported chronic P.malariae infection was linked to nephrotic
the rarity of relapses in naturally acquired infections syndrome in Nigerian children about 50 years ago, and
and hypothesized that some of these cases might be it is believed to be caused by immune complex
due to P.vivax misidentified as P.ovale.73 Moreover, deposition on the basement membrane.81,82 The young
they claimed that in P.ovale infection, hypnozoites trophozoites are similar to those of P.vivax (although
have never been demonstrated by biological their cytoplasm is thicker and they stain more deeply);
experiments but in their paper failed to cite the work by a characteristic feature of P.malariae is the appearance
Garnham.72,73 After treatment of a primary attack the of band form with the trophozoite that stretch across
relapse interval for P.ovale has been described to be in the entire width of the cell. The mature schizont has an
the range of 17 to 255 days;71 however, delayed average of 8 merozoites that are sometimes arranged
primary attacks have been observed after as long as 4 symmetrically around the centre with a daisy
years and in a recent paper of mostly PCR confirmed appearance.1 The sporogonic cycle in the Anopheles
cases of P.ovale , a primary attack was observed after mosquito takes 30-35 days at 20°C but may be as short
53 months.74,76 as 14 days at 28°C.
Recently in a study conducted in Cameroon, Duval
and coworkers found for the first time two Plasmodium knowlesi. Plasmodium knowlesi (Sinton
chimpanzees infected by human P.ovale a condition and Mulligan 1932) is a simian plasmodium that was
that raise the possibility that cross-species exchange probably first described by the Italian malariologist
might be more important than previously thought with Giuseppe Franchini in the blood of Macaca
the potential role of African great apes as reservoir for fascicularis. 83,84 Subsequently it was studied by
human malaria parasites.77 Napier, Campbell, Das Gupta and Knowles and finally
was completely characterized by Sinton and Mulligan
Plasmodium malariae. Plasmodium malariae who named it P.knowlesi in honour and acknowledging
(Laveran, 1880), responsible of the “quartan malaria”, the original work of Dr Knowles.85-87 P.knowlesi was
is present worldwide in all major malaria-endemic employed in the treatment of general paresis of insane
regions but with a scattered distribution.70,78 Infections (i.e. neurosyphilis) until 1955 when it was finally
caused by P.malariae are most common in sub- abandoned due to the increased virulence of the
Saharan Africa and southwest Pacific and less organisms after multiple passages in humans.85,88 The
frequently encountered in Asia, Middle East, Central first natural infection of humans was serendipity
and South America. As for P.vivax also for P.malariae observed in an American Army patient who was
the relationship between the life cycle of development deployed in Peninsular Malaysia and developed
(respectively 48- and 72-hours) and the periodicity of malaria on the way home.89 The availability of
the fever paroxysm were elegantly explained by molecular diagnostic tools recently helped to
Camillo Golgi in 1886 although the two parasites were distinguish P.knowlesi from P.malariae and to identify
identified as separate species by Grassi and Feletti.43,44 it as an important cause of human malaria not only in
The parasite is characterized by a slow development the Peninsular Malaysian Borneo but also in other parts
either in the Anopheles mosquito (15 days) and in of South-east Asia.2,90 Phylogenically, P.knowlesi is
human (15 days in the liver, 72 hours in the blood). more closely related with P.vivax than other humans
P.malariae is considered to be the precursor of Plasmodia and in a similar way the process of
P.brasilianum a parasite that infects New World merozoites invasion of erythrocytes requires the
monkeys and has naturally adapted to it;1,78 both interaction of Duffy-bindings proteins (DBP) with the
Plasmodia are able to infect either humans and Duffy antigen receptor for chemokines (DARC).1,91,92
monkeys. P.malariae is responsible of low grade However, important phenotypic differences with
parasitaemia , rarely exceeding 30,000 parasites per P.vivax exists such as absence of a dormant liver stage,
microliter, probably as a consequence of the low host blood cell preference and length of asexual cycle.
number of merozoites produced per erythrocytic cycle The genome of P.knowlesi has been sequenced and
together with the 72-hour developmental cycle and the described showing important differences with those of
preference to infect older erythrocytes. The pre-patent P.falciparum and P.vivax (Table 3).93 P.knowlesi was
period for P.malariae is extremely variable with a the first malaria parasite in which antigenic variation
range of 16 to 59 days. No quiescent liver stage forms was demonstrated to occur.94
have been identified for P.malariae but this parasite is Long-tailed (Macaca fascicularis) and pig-tailed
able to persist in the blood with low level parasitaemia macaques (M.nemestrina) are the main natural hosts of
for extremely long periods and perhaps for the entire P.knowlesi.85 After infection, all the developmental
life of the human host causing recrudescence even after stages of the malaria parasite life-cycle are observed in

Mediterr J Hematol Infect Dis 2012; 4: Open Journal System

the peripheral blood. The intra-erythrocitic life-cycle is
of 24 hours (unique for all malaria parasite of primates) Conclusions. Our knowledge of the biology of human
with an asynchronous development and it is not malaria parasites has dramatically improved in the last
restricted to young or old cells.85,89 The young ring few years thanks to the whole sequencing of DNA of
forms appear very similar to those of P.falciparum the two most important human Plasmodia:
whereas during subsequent stage of maturation the P.falciparum and P.vivax. Moreover, the introduction
intra-erythrocyte parasites resemble the band forms of molecular techniques has greatly improved the
observed in P.malariae infection.2,85 The mature identification of malaria parasites at the species level.
schizont contains as many as 16 merozoites with an In this regard , the availability of species-specific
average of 10. The sexual forms grow more slowly polymerase chain reaction allowed Balbir Singh and
than asexual forms and take usually 48 hours to his coworkers to recognize the significant role of
complete their development; the macrogametocyte at P.knowlesi, a natural plasmodia of macaques, as a
the end of maturation is spherical with a blue-stained cause of human malaria in the Southeast Asia. This
cytoplasm and fills the host cell whereas the discovery, together with the possibility to use non-
microgametocyte is sometimes smaller and with a invasive methods to supply animal DNA, renewed the
pink-stained cytoplasm. High level of parasitemia and interest to study malaria parasite of apes increasing the
severe manifestations resembling those of P.falciparum membership clade of P.falciparum and P.ovale and
malaria have been described for P.knowlesi with a finally showing that P.falciparum is diverse and not
possible lethal outcome.94,95 human-host restricted.

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