British Medical Bulletin (1982) Vol. 38, No. 2, pp.
117-122
LIFE-CYCLE OF PRIMATE MALARIA PARASITES R S Bray & P C C Garnham
THE LIFE-CYCLE OF PRIMATE
MALARIA PARASITES
R S BRAY PhD DSc
P C C GARNHAM CMG MD DSc FRS
Department of Pure and Applied Biology
Imperial College of Science and Technology
London
1 General features of the life-cycle of primate malaria
parasites
a Introduction of sporozoites and exoerythrocytic
schizogony
b Cycle in the blood
c Development in anopheline mosquitoes
d Relapses
2 Special features of important species
a Plasmodium (Plasmodium) vivax
b Plasmodium (Plasmodium) ovale
c Plasmodium (Plasmodium) malariae
d Plasmodium (Laverania)falciparum
e Plasmodium (Plasmodium) cynomolgi and subspecies
/ Plasmodium (Plasmodium) knowlesi
References
1 General Features of the Life-Cycle of Primate Malaria
Parasites
We wish to emphasize two factors which are of primary
importance in the study of primate malaria: (0 the alternation of
two hosts—vertebrate and invertebrate—in the life-history of
the parasite in which three steps occur, two intracellular in the
vertebrate and the third extracellular in the anopheline mosquito.
Both sexual and asexual growth and division occur; (ii)
chronobiology. The timetable of events in all stages is highly
significant, for clinical diagnosis, for taxonomic differentiation to
subspecies and as a survival mechanism for the parasite.
a Introduction of Sporozoites and Exoerythrocytic Schizogony
When a female anopheline mosquito infected in the salivary
glands with a primate malaria parasite (Plasmodium spp.) bites,
the sporozoites in the saliva are injected by the proboscis as it
probes in the skin. It is not known whether the mosquito feeds
directly from a capillary or from a pool formed by the probing
proboscis or, if from a capillary, whether the proboscis is
introduced upstream or downstream in the capillary. In any
case there is no doubt that the sporozoites reach the blood
stream quickly and efficiently and few are carried into the
lymphatic system (see Bray, 1981).
The sporozoites circulate in the blood stream for an hour at
the most but probably for much less (Fairley et al. 1947; Sinden
& Smith, 1982). Their pathway from blood to liver hepatocyte,
where they can be found 40 hours later in the case of P.
cynomologi bastianellii of macaque monkeys (Krotoski et al.
1982), is a matter of conjecture. Two pathways have been
suggested, one in which the sporozoite is taken up by a Kupffer
cell and spends some time there before actively leaving that cell
and invading a hepatocyte (Verhave et al. 1980; Smith et
117
al. 1981), and the other in which the sporozoite evades the
Kupffer cell and enters a hepatocyte directly (Shortt, 1948).
Finally there is the possibility of active invasion of a hepatocyte
via an endothelial lining cell. By 40—48 hours tiny malaria
parasites 3 urn in diameter, consisting of a single nucleus and a
little cytoplasm, can be found in hepatocytes (Shortt et al. 1954;
Krotoskiera/. 1980, 1981, 1982).
Three days after infection these intrahepatocytic forms may
or may not have differentiated into schizonts or hypnozoites
(latent forms of tissue stages), depending on whether the species
of malaria parasite causes true relapses or not. Hypnozoite
development will be considered in section Id.
The exoerythrocytic schizonts' growth is accompanied by
nuclear division and an increase in cytoplasmic volume. Mature
schizonts may measure 30-70 urn in diameter and grossly
enlarge their host cell, pushing the hepatocyte nucleus to one
side and frequently flattening it. No reaction is caused in the
liver until the schizont bursts. At maturity a piece of cytoplasm
joins with each nucleus to form daughter parasites—the
merozoite—measuring about 1 um in diameter. The schizont
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and host cell then rupture, releasing merozoites into the blood
stream (Garnham, 1966).
b Cycle in the Blood
The merozoites from the liver are probably short-lived and
must find and enter an erythrocyte within minutes. Merozoites
contain an apical complex including organelles which, after
orientation, come into contact with a site on the erythrocyte
surface, which is probably a specific receptor for that species of
malarial merozoite. The merozoite organelles induce in-
vagination of the erythrocyte surface and the merozoite enters
the erythrocyte via the invagination possibly by capping; that is
the merozoite maintains the original points of contact between
itself and the erythrocyte membrane and moves these points of
contact back along its own surface membrane and slips into the
erythrocyte. The merozoite has an envelope consisting of an
outer plasma membrane and two inner membranes and acquires
a surface coat while in the plasma. On entering the erythrocyte
it loses the two inner membranes and sheds the surface coat.
After entry into the erythrocyte, the merozoite develops a
vacuole and becomes a ring form, shaped like a signet ring, with
the nucleus as the seal. The ring grows by increasing the
cytoplasm until the vacuole disappears; the cytoplasm may
remain compact or become amoeboid, and pigment—a break-
down product from haemoglobin—appears in the cytoplasm.
The parasite feeds on the erythrocyte by encircling and taking in
small amounts of erythrocytic cytoplasm which is largely
haemoglobin. Digestion occurs within food vacuoles, with the
production of the typical yellow brown to black malarial
pigment particles as an end-product (see Table I). At this stage
the parasite is known as the trophozoite. The next stage, the
schizont, is heralded by the division of the nucleus, which it is
assumed has increased its DNA content and become X-ploid,
where X is the eventual number of daughter cells to be
produced. The nucleus divides three to five times to form 8—32
nuclei (see Table I). At this stage the parasite occupies much or
all of the erythrocyte and the pigment tends to concentrate into
a single mass. Possibly the feeding process may cause small
pieces of the parasite to be broken off and left at the site of
feeding near the plasmalemma of the erythrocyte, and it may be
these pieces that stain with Romanovsky stains to give the
characteristic stippling to the host erythrocyte caused by many
primate malaria parasites (see Table I).
 LIFE-CYCLE OF PRIMATE MALARIA PARASITES R S Bray & P C C Garnham

TABLE I. Some comparative and diagnostic characters of the four human malaria parasites
P. faldparum P vfvax P. ovah P malarias

Duration of primary exoerythrocytlc cycle (days) 51 8 9 14-15

Prase nee of hypnozofltea + + —
Number of exoerythrocytlc meroioltes 30000 10000 15000 15000
Enlargement of nucleua of hepatocyte _ _ + +
Average diameter of mature exoerythrocytlc schlzont (pun) 60 46 60 65
Duration of erythrocytic cycte (nouns) 48 48 50 72
Nature of the host erythrocyte Young Retlculocytes and Retlculocytes and Normocytes
young normocytes. young normocytes
Duffy group positive
Enlargement of hoot erythrocyte — ++ + —
Stippling of host erythrocyte Maurer's clefts Schuff ner's dots Schuffner's dots Zlemann's stippling
Pigment colour Black Yellow—brown Dark brown Dark brown to black
Number of erythrocytic merozoltei 8-32 8-24 4-8, 8
occasionally 16
Shape of gametocytes Crescent Round Round Round
Duration of mosquito cycle at 27 °C (days) 10 8-9 12-14 14-16
Pigment pattern in oocysts Chains and rows Prince of Wales feathers Crossed lines Clustered late on
periphery
Diameter of mature oocyst (nm) 55 50 45 40

The maturation of the schizont and the production of chemotaxic gradient, it penetrates the macrogamete and the two

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merozoites occupy an interval of time characteristic of each
species of malaria parasite and lasting 24, 48 or 72 hours, thus
giving rise to the typical quotidian, tertian and quartan
periodicity (see Table I). The merozoites containing a single
nucleus are budded off from the schizont, leaving a residual
body containing the pigment. At this time the host erythrocyte
disintegrates, releasing merozoites and residual body into the
plasma. The residual body is phagocytosed mostly by fixed-
tissue macrophages and the merozoites in the non-immune host
invade new erythrocytes.
After one or more cycles in the blood the sexual phase of the
parasite begins. The exact stimulus is unknown. The nucleus
becomes diploid in the macrogametocyte (female) and octoploid
in the microgametocyte (male). The gametocytes are usually
round (crescentic in one case), contain a single nucleus and
scattered pigment; when mature they fill the host erythrocyte.
They also give rise to the stippling of the host erythrocyte
typical of the species.
Hawking et al. (1968) showed that, in synchronous infections
of several species of Plasmodium, gametocytes matured during
the night and suggested that this represented a device whereby
their presence in the blood at this time coincided with the biting
habits of the nocturnal anopheline mosquitoes.
c Development in Anopheline Mosquitoes
The sexual cycle is completed when a suitable species of
mosquito bites the individuals in whose blood mature
gametocytes are circulating. The macrogametocyte escapes
from the erythrocyte and becomes a free macrogamete in the
lumen of the mid-gut of the mosquito; the nucleus undergoes
reduction division. The microgametocyte undergoes internal
organization, including spindle formation, and then emerges
from the erythrocyte, and its nucleus undergoes a series of
extraordinarily rapid divisions (Sinden, 1981) to form eight new
nuclei. From the cytoplasm eight filaments are extruded, each
equipped with a flagellum, and into these filaments the nuclei
migrate completing the formation of the microgametes. This
process takes about 10-20 minutes after blood is ingested by the
mosquito and is induced by various factors, including tempera-
ture and CO 2 partial pressure. The microgamete, once formed,
breaks off from the now shrunken body of the former
microgametocyte and moves off driven by the flagellum in
search of the macrogamete. When the haploid microgamete
finds a haploid macrogamete, perhaps by moving along a
nuclei fuse, probably within minutes, to form a diploid zygote.
The zygotes, still containing the pigment of the macro-
gametocyte, elongate over the next 12 hours and move through
the blood clot to the gut epithelium of the mosquito. Between 24
and 48 hours after fertilization the zygotes, known as ookinetes,
penetrate the gut epithelial cells and come to rest between the
gut epithelial cell layer and the basal lamina that covers the gut
on the coelomic cavity side. About two to three days after the
infective blood meal the ookinetes have secreted a thin cyst wall
and probably undergone meiotic division to become haploid
oocysts. The nucleus must now organize its DNA in order to
undergo the number of schizogonic-like divisions necessary to
form up to 10000 daughter cells. Such a process resembles in
some ways the exoerythrocytic schizogony in the next stage of
the cycle. The oocyst will undergo repeated nuclear divisions at
a rate dependent upon the species of malaria parasite and the
temperature (see Table I). The pigment, which can be seen in
fresh young oocysts before repeated division obscures it, lies in
patterns typical of the species (see Table I). During nuclear
division of the oocyst the cytoplasm is thrown into an
anastomizing sponge-work and eventually the nuclei are
arranged along the surface of this network. Instead of a
sponge-work, the contents of the oocyst are in some species
condensed into spheres 4 or 5 urn in diameter, and resemble the
sporoblasts described by the earlier workers. From the surface
of the network or of the sporoblasts, small protrusions form into
which a nucleus and other organelles pass; in this way the fine
sporozoites are developed. The latter are slightly curved and
about 11-14 urn long; they eventually become free and emerge
into the haemocoelomic cavity, through rents in the old oocyst
wall.
These free sporozoites are carried all over the mosquito by the
haemocoelomic fluid but concentrate, probably under chemotaxic
control, in the salivary glands of the mosquito. Here by a totally
unknown process they invade the acinal cells of the salivary
glands and mature into infective forms. They then penetrate
further into the salivary glands and appear in the ramifications
of the salivary duct where they are able to infect the next
primate that the mosquito bites, by flowing with the saliva into
the wound.
d Relapses
The malaria parasites of primates that cause true relapses are
P. vtvax and P. ovale of man and a number of malaria parasites

118
 LIFE-CYCLE OF PRIMATE MALARIA PARASITES R S Bray & P C C Garnham

FIG. 1. Exoarythrocytic development of various primate malaria parasites

Rfaldpanim

Rovala

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RvWax NIcoiMvi Moscow strain (R v. hibarnans)

Rvtvax North Korean strain

-M-

• « / » • - • Wood rhmtr, (R)

Rylvax St.EIzab*th,Madagascar,North M a n itraint

Rv1va« Chasaon atrafn (and Rcynomotgl, P.fWdl, Rslmlovata)

0 U 24 tim !• 4«

The thickness of the horizontal lines is Intended to indicate the proportion of the sporozoites that differentiate into immediately growing
schizonts or into the various populations of hypnozoites destined to cause relapses. All timings, other than the immediately growing
schizogony cycle, are necessarily approximate or even notional
(R): relapse if a primary attack has occurred
(P): primary attack if an early primary attack has not occurred

119
 LIFE-CYCLE OF PRIMATE MALARIA PARASITES R S Bray & P C C Garnham

of apes and monkeys, which share with P. vivax and P. ovale
the characteristics of a 48-hour blood cycle and Schuffner's dots
on the infected erythrocyte surface (Garnham, 1977). We
define a true relapse as renewed parasitaemia following a period
in which the blood contains no detectable parasites. Malaria
parasites for which no evidence exists for relapses and whose
sporozoites are thought not to differentiate into hypnozoites in
the liver include P. falciparum and P. malariae of man, P.
reichenowi of apes, and the quotidian and quartan (72-hour
blood cycle) malaria parasites of monkeys. In these parasites
we believe all sporozoites develop directly into hepatic schizonts.
The sporozoites of the relapsing malaria parasites differen-
tiate into either hypnozoites or developing schizonts in varying
proportions, depending upon the species and strain (see section
2a and fig. 1). The hypnozoites remain dormant as single-
nucleated intrahepatocytic round bodies of about 4—5 urn in
diameter. We believe that at the predetermined time for a
relapse (e.g. 8—10 months in temperate-zone P. vivax infections)
the population of hypnozoites destined to bring about the
relapse commences to grow and undergoes exoerythrocytic
schizogony, forming merozoites that invade the blood. "Reac-
tivated" or "relapse" schizonts were first described by Shortt &
Garnham (1948) in P. cynomolgi infections and have since been
seen by other observers. In recent experiments, Krotoski et al.
(1982) have described "relapse" schizonts varying from 16 urn
to 38 urn in diameter at 50 and 105 days after sporozoite
infection.
Additional populations of hypnozoites, in our belief, will
cause further relapses, with the blood becoming clear of
parasites between relapses. The number of populations of
hypnozoites and the number of hypnozoites per population will
vary with the strain and species of parasite involved and its
characteristic relapse pattern (see fig. 1).
The characteristics of the human malaria parasites are
tabulated in Table I. Figure 2 shows the life-cycle of a primate
malaria parasite in diagrammatic form.

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FIG. 2. The life-cycle of a primate malaria parasite

1: sporozoites Injected into skin by the mosquito; 2: 2-day-old exoerythrocytic form in a hepatocyte; 3, 4, 5: growing exoerythrocytic
schizonts; H: hypnozoites in hepatocytes; 6: mature exoerythrocytic schizonts bursting, releasing merozoites into the blood; 7: erythrocyte;
8, 9: growing trophozoites; 10, 1 1 : growing schizonts; 12: mature schizont releasing merozoites; 13, 14, 15, 16, 17: erythrocytic cycle
repeated; 18, 19: growth of the microgametocyte; 20, 2 1 : growth of the macrogametocyte; 22: mosquito has taken gametocytes up into
its mid-gut; 23: exflagellation of the microgametocyte; 24: macrogametocyte escapes from erythrocyte to become a macrogamete; 25:
microgamete; 26: macrogamete about to be fertilized; 27: zygote or ookinete; 28, 29, 30: oocyst growth on the mid-gut surface; 3 1 :
odcyst bursting, releasing sporozoites; 32: sporozoites in the mosquito salivary glands

120
 LIFE-CYCLE OF PRIMATE MALARIA PARASITES R S Bray & P C C Garnham
2 Special Features of Important Species
Some of the characteristic features of the life-cycle of two
groups of parasites are discussed below: the characteristic
human species P. vivax, P. ovale, P. malariae and P.falciparum
and the simian species that occur rarely as human zoonoses and
that have also been used extensively as models of human
malaria in research (P. cynomolgi and P. knowlesi).
a Plasmodium (Plasmodium) vivax
This species is a relapsing parasite causing benign tertian
malaria of man; it has a largely subtropical distribution though
it occurs frequently in South-East Asia and New Guinea. Its
sporozoites differentiate in the liver into schizonts or hyp-
nozoites. The schizonts grow for 8 days and then produce
merozoites, which produce a primary clinical malaria attack
usually about 15 days after the introduction of sporozoites.
Some northern strains of P. vivax, such as the Russian strains of
Nicolaev (1949) and Tiburskaja et al. (1968) (so-called P. vivax
hibernans), and the Hainan (China) strains (so-called P. vivax
multinucleatum) may have few, or no, sporozoites which form
schizonts immediately so that early primary attacks are
unknown (see fig. 1). Tropical strains tend to show a number of
randomly distributed relapses following an early primary attack.
Intermediate subtropical strains may or may not show an early
primary attack and will usually have a late primary attack or a
relapse at about 9 months after infection. Obviously these
patterns fit the seasonal activity of Anopheles of the area.
Figure 1 shows how we presently think the various strains of P.
vivax sporozoites develop.
During the erythrocytic development of P. vivax all forms
can be found in the peripheral blood. Merozoites of P. vivax
have a receptor that attaches to a site upon young human
erythrocytes, which is (or is associated with) the Fy Fy (Duffy
group) antigen, so only Duffy-group-positive individuals suffer
P. vivax malaria (Miller et al. 1976). This is the basis for the
innate resistance of subjects of pure Negro lineage who are
uniformly Fy Fy — ve. P vivax greatly enlarges its host erythro-
cyte and causes it to become regularly stippled when stained. It
forms golden-brown pigment and its gametocytes are round.
b Plasmodium (Plasmodium) ovale
This species is another relapsing parasite of man which
resembles P. vivax. It is largely confined to Africa and its
relapse patterns are not well known. It differs from P. vivax in
having a nine-day liver schizogony where it enlarges the host
hepatocyte nucleus (see Table I) and in causing an oval
distortion of its host erythrocyte during the making of thin blood
smears, which can be preserved and used as a diagnostic tool if
the blood smear is dried quickly. It also possesses slightly larger
and more irregular nuclei, produces eight nuclei as a rule in the
primary attack and displays dark brown pigment in the
erythrocytic phase. In the oocyst stage it shows two lines of
pigment usually crossed.
c Plasmodium (Plasmodium) malariae
This species, causing quartan malaria of man, used to be of
cosmopolitan distribution, though it tended to be common in
certain parts of the world, e.g. tropical Africa, Guyana and parts
of India. It is a natural parasite of the chimpanzee in which it
was originally named P. rodhaini, now regarded as a synonym
of P. malariae. The quartan parasite of South American
monkeys, P. brasilianum, is thought by many workers to
represent the result of the introduction of P. malariae in the
121
past two or three centuries into the New World by immigrants
from Europe and West Africa; the strain then became adapted
to the local monkey and gradually spread through the forest
The life-cycle and morphology of the two parasites appear to be
identical, and man and South American monkeys are suscep-
tible to both (Coatney et al. 1971). The anopheline vector of .P.
rodhaini (= P. malariae) is unknown; it seems that in
present-day conditions man would not be bitten by sylvatic
mosquitoes and thus a zoonosis does not occur. Under
laboratory conditions P. brasilianum (= P. malariae) is easily
transmitted to man by the bite of infected mosquitoes.
The quartan periodicity of this parasite in the blood is
reflected by the long duration of sporogony in the mosquito and
exoerythrocytic schizogony in the liver (see Table I). The
persistence of the parasite for many years, perhaps even for a
lifetime, was thought to denote a long succession of relapse
cycles in the liver. The relapse cycle in other forms of malaria is
now known to be solely initiated by sporozoites. No late
"relapse" exoerythrocytic stages have been detected in livers
infected with quartan parasites. The infection is as persistent
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after inoculation with infected blood as with sporozoites. Both
the original attack and the relapses are easily cured by
schizontocidal drugs such as chloroquine. Individuals with no
symptoms frequently infect recipients when acting as blood
donors. All these factors confirm that persistent hypnozoites in
the liver do not occur in P. malariae infections or infections with
other quartan parasites.
None of the quartan parasites enlarge their host erythrocytes
and all cause Ziemann's stippling of the erythrocyte, a
dust-like blush, on heavy Romanovsky staining. The exo-
erythrocytic schizont causes enlargement of the host hepato-
cyte nucleus.
d Plasmodium (Laverania) falciparum
This parasite belongs to a different subgenus by virtue of the
crescentic shape and lengthy development of its gametocytes. It
does not cause relapses, and renewed activity in P. falciparum
infections springs from persisting if undetected erythrocytic
infections and is called a "recrudescence". The parasite causes
malignant tertian malaria, and, as the name implies, may kill. It
is a largely tropical parasite and is the great scourge of Africa
and South-East Asia.
All the sporozoites of P. falciparum develop directly into
schizonts, and hypnozoites do not occur (see Table I and fig. 1).
The liver schizogony occupies 5$ days and schizonts reach
50 um in diameter. The erythrocytic schizogony occurs in the
blood space of inner organs. The ring forms appear in the
peripheral blood after merozoite invasion of young erythrocytes
and persist there until just before the black pigment appears. At
this stage a stippling known as Maurer's clefts appears, which
when stained shows as streaks, commas or large dots. The para-
sitized erythrocyte then disappears from the peripheral blood
and will reappear only when containing a new ring form or a
fully mature crescentic gametocyte. Further development occurs
in the capillaries of the spleen, liver, lung, heart, brain and other
organs and notably in the intervillous spaces of the placenta in
the pregnant woman who is more susceptible to infection with
this parasite. The cause of this sequestration may be an
adherence between distortions on the infected erythrocyte
surface and endothelial lining cells (Luse & Miller, 1971;
Aikawa, 1977), though this cannot be the case in the placenta
(Bray & Sinden, 1979). The means of retention of the
developing gametocyte is unknown. The gametocyte of P.
 LIFE-CYCLE OF PRIMATE MALARIA PARASITES R S Bray & P C C Garnham
falciparum takes about 10-11 days to develop, as opposed to
about two days for P. vivax. When mature it appears in the
peripheral circulation and is available for uptake by a female
mosquito.
e Plasmodium (Plasmodium) cynomolgi and Subspecies
P. cynomolgi of Asian macaque monkeys closely resembles P.
vivax in all respects, and the type and its subspecies P. c.
bastianellii form ideal models for certain strains at least of the
human parasite. So much so, that laboratory transmission from
monkey via mosquitoes to man took place first accidentally then
deliberately in both the USA and England. The parasite is so
infectious to man that it seems zoonotic transmission must be
common in the enzootic areas in South-East Asia, though
infection has not been reported. The human disease is mild and
might well remain unrecognized.
The blood stages of P. cynomolgi are slightly less amoeboid
and smaller than those of P. vivax. Exoerythrocytic schizogony
is slightly faster.
The discovery by Krotoski et al. (1980, 1982) of the
hypnozoite and its significance relative to relapses (discussed in
section Id) was made using P. c. bastianellii. As P. cynomolgi,
like P. vivax, is unable to infect Negroes it can be assumed that
its merozoites like those of P. vivax and P. knowlesi invade
erythrocytes via a receptor which is, or is associated with, the
Duffy group antigen site.
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f Plasmodium (Plasmodium) knowlesi
This common parasite of South-East Asian kra monkeys is
unique among the primate species in possessing a quotidian
(24-hour) periodicity in the blood. For this and other reasons (h
is sequestered to some degree in inner organs) its pathogenicity
to unnatural hosts such as the rhesus monkey is extremely high;
the rapid erythrocytic schizogony in the blood causes the
infection to build up so quickly that effective immunity has no
time to develop and the rhesus monkey dies from a fulminating
parasitaemia.
The duration of the exoerythrocytic schizogony is also
shorter (5$ days) than that of similar stages in other primate
species of the subgenus Plasmodium. P. knowlesi is not a
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also short (8-9 days). The blood stages do not enlarge the host
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P. knowlesi is a proved zoonosis (Chin et al. 1965); an
American soldier became infected in the Malayan jungle and
developed malaria about 10 days later. This species has in the
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past been used for malaria therapy and after about 170 blood
passages became highly virulent for man, although in earlier
transfers the pathogenicity for man was low.
ACKNOWLEDGEMENTS
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