Introduction:
History of Plasmodium Parasites
Malaria parasites have been with us since the dawn of time.
They probably originated in Africa (along with mankind) and fossils of
mosquitoes up to 30 million years old show that the vector for malaria
was present well before the earliest history.
The Plasmodium parasites are highly specific, with man as the only
vertebrate host and Anopheles mosquitoes as the vectors.
This specificity of the parasites also points towards a long and
adaptive relationship with our species.
At present, at least 300,000,000 people are affected by malaria
globally, and there are between 1,000,000 and 1,500,000 malaria deaths
per year .
Malaria is generally endemic in the tropics, with extensions into the
subtropics.
Malaria in travellers arriving by air is now an important cause of
death in non-malarious areas, and this is not helped by the common
ignorance or indifference of travellers to prophylaxis.
Distribution varies greatly from country to country, and within the
counties themselves, as the flight range of the vector from a suitable
habitat is fortunately limited to a maximum of 2 miles, not taking
account of prevailing wind etc.
The map indicates current distribution of indigenous malaria according
to WHO:
In 1990, 80% of cases were in Africa, with the remainder clustered in
nine countries: India, Brazil, Afghanistan, Sri-Lanka, Thailand,
Indonesia, Vietnam, Cambodia and China.
Current data for Africa is unavailable.
The disease is endemic in 91 countries currently, with small pockets
of transmission in a further eight.
Plasmodium falciparum is the predominant species, with 120,000,000
new cases and up to 1,000,000 deaths per year globally.
It is the Plasmodium falciparum species which has given rise to the
formidable drug resistant strains emerging in Asia.
In 1989, WHO declared malaria control to be a global priority due to
the worsening situation, and in 1993, the World Health Assembly urged
member states and WHO to increase control efforts.
As well as control measures, such as spraying with DDT, coating
marshes with paraffin (to block Anopheles mosquito larvae spiracles),
draining stagnant water, and the widespread use of nets, research into
the biology and microbiology of malaria enables a methodical search
for better vaccines and a possible cure in the fight against malaria.
Biology of Plasmodium Parasites and Anopheles Mosquitos
The Plasmodium genus of protozoal parasites (mainly P.falciparum,
P.vivax, P.ovale, and P.malariae) have a life cycle which is split between
a vertebrate host and an insect vector. The Plasmodium species, with the
exception of P.malariae (which may affect the higher primates) are
exclusively parasites of man. The mosquito is always the vector, and is
always an Anopheline mosquito, although, out of the 380 species of
Anopheline mosquito, only 60 can transmit malaria. Only female mosquitos
are involved as the males do not feed on blood. The basic life cycle of
the parasite is shown below:
The spozozoites from the mosquito salivary gland are injected into the
human as the mosquito must inject anticoagulant saliva to ensure an even
flowing meal. Once in the human bloodstream, the sporozoites arrive in
the liver and penetrate hepatocytes, where they remain for 9-16 days,
multiplying within the cells. Next they return to the blood and
penetrate red blood cells, in which they produce either merozoites,
which reinfect the liver, or micro- and macrogametocytes, which have
no further activity within the human host. Another mosquito arriving to
feed on the blood may suck up these gametocytes into its gut, where
exflagellation of microgametocytes occurs, and the macrogametocytes are
fertilized. The resulting ookinete penetrates the wall of a cell in the
midgut, where it develops into an oocyst. Sporogeny within the oocyst
produce many sporozoites and, when the oocyst ruptures, the sporozoites
migrate to the salivary gland, for injection into another host.
This highly specialised life cycle requires specialised biology
on the part of the Plasmodium species. The reason that not all
mosquitos are vectors for Plasmodium parasites is that refractory
mosquitos posses substances toxic to Plasmodium within their cells .
A higher trypsin-like activity was also found in the midgut of resistant
species, possibly inhibiting ookinete development. Plasmodium parasites
seem capable of adapting to any suitable anopheline mosquito, given
sufficient time and contact. Sporogeny within the mosquito are
governed by environmental temperature as Anopheline mosquitos are
poikilotherms.
Once injected into the human host, all Plasmodium species will
penetrate hepatocytes. However, P.falciparum and P.malariae sporozoites
trigger immediate schizogony whereas P.ovale and P.vivax sporozoites
may either trigger immediate schizogony or have a delayed trigger,
resulting in dormant hypnozoites. Some strains, such as the North
Korean strain, seem to consist of sporozoites with universally delayed
triggers, so they all form long lasting hypnozoites. P.vivax may have
an incubation period of up to 10 months. Gametocytes produced in the
primary attack seem to contain all the genetic information required to
create sporozoites of several different activation times. The same
seems true for gametocytes produced in relapses where the hypnozoites
become activated.
Sexual development of Plasmodium begins as the merozoites invade the
erythrocytes after their release from the liver. Within the erythrocyte,
shizogony occurs to produce either more merozoites (taking 22 1/2 hours
in the case of P.berghei), or the sexual micro and macrogametocytes
(taking 26 hours). In P.falciparum, erythrocytic schizogony takes
48 hours and gametocytosis takes 10-12 days. Normally a variable number
of cycles of asexual erythrocytiic shizogony occurs before any gametocytes
are produced . The immune system may produce antibodies to the
gametocytes at this stage.
Once drawn into the mosquito, the gametocytes increase in volume and
escape the erythrocyte. Microgametes are formed by 3 mitotic divisions
within the microgametocyte, and are expelled explosively.
No further changes affect the female macrogametocyte until fertilisation
where the plasmalemmas of male and female gametes fuse and the nucleus
of the microgamete enters the female cytoplasm. After fertilisation,
the zygote is a motionless globular cell, but after 18 to 24 hours it
becomes elongated and motile, containing micronemes and a pellicle.
The cell invades the microvillus border, passes through the midgut cells,
and lies beneath the basement membrane. The ookinete then becomes a
static oocyst, between the basal lamina and the basement cell membrane,
and bounded by a thick plasmalemma. The chief source of nutrients is
the haemolymph in which the oocyst develops. Sporoblasts form, and
sporozoites bud off.
After the cyst ruptures, the sporozoites escape into the
haemocoele and migrate to and penetrate salivary gland cells, where
they lie in vacuoles for up to 59 days. These sporozoites develop and
become up to 1000 times more infective than when in the oocyst. They
are more antigenic, and bear circumsporozoite polypeptide on their
plasmalemma. Sporozoite motility is involved in their invasion of cells
and escape from the salivary gland. The sporozoites are about 12µm
long and 1µm across, with a single nucleus, anterior to which lie
micronemes, and posterior to which lies ER and mitochondria. They posses
a complex pellicle, which is responsible for motility, and this pellicle
contains circumsporozoite protein. The apical penetrating region
contains extensions of the microneme ducts which release an agent which
interacts with host cell plasma membrane during penetration.
A biting mosquito transfers about 10% of its sporozoite load
into the capillaries or perivascular tissue. Now the sporozoites must
begin their evasion of the host defences, possibly by binding serum
proteins for 'camouflage'. Some are destroyed by macrophages, or by
antigen-specific antibodies in immune individuals, but in non-immune
individuals, they reach the hepatocytes and initiate schizogeny or
become hypnozoites depending on their delay trigger. All sporozoites
have left the peripheral circulation system within 45 minutes.
The Walter and Eliza Hall Institute Malaria Database
The Walter and Eliza Hall Institute(WEHI)
is involved in the microbiological analysis of the malaria species.
The DNA mapping of the 14 chromosomes and the discovery of genes,
antigens, and their functionality provide vital clues to help us find
a means to combat the spread of malaria.
A species' genome is all the genetic material in the species' chromosomes.
A genome project is the collecting and collating of such information,
and a genome database is the storage of the information with searching
for sequences, clones, isolates, papers, etc., facilities.
The malaria genome project at the Walter and Eliza Hall Institute
(WEHI) has been going since 1983, and the developement of a Malaria
database (MalDB) using the stucture of the A. C. elegans database(ACeDB) has been underway since
December, 1996.
Information concerning the Malaria genome project can be found from
the Malaria Database home page.
Also, from the home page, can be found links to other databases such
as the SRS browser and
the Codon
Usage Database.
Links to a Malaria discusion group, other malaria and parasitology
sites, and other miscellaneos information can can be found from the
home page.
The above introduction is, for the most part, an extraction from a
very informative document on malaria that can be found at the
URL address http://www-micro.msb.le.ac.uk/Bradley/Bradley.html.
This is copyright information and is reproduced with the permission of
Dr Alan J. Cann PhD, Department of Microbiology & Immunology,
University of Leicester, P. O. Box 138, Medical Sciences Building,
University Road, Leicester LE1 9HN, UK.
© Titus Bradley and
Department of Microbiology and
Immunology, University of Leicester
1996.
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